THE TRUTH ABOUT HYDRAZINE SULFATE – DR. GOLD SPEAKS

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http://www.hydrazinesulfate.org/

 

 

 

THE TRUTH ABOUT HYDRAZINE SULFATE – DR. GOLD SPEAKS

 

July 14 , 2004

Last amended: June 16, 2005

 

For some time now I have refrained from making any comments in regard

to information on the Internet concerning hydrazine sulfate. My

silence has been occasioned by the hope that our federal and prominent

private-sector cancer agencies would endorse the use of hydrazine

sulfate, in the wake of clinical trials demonstrating its

effectiveness in the treatment of cancer.

 

But this hasn't happened. Quite the opposite. A casual examination of

the Internet shows that information in regard to hydrazine sulfate is

composed of a mixture of " endorsements " of hydrazine sulfate from

individual patients and their advocates—and the seemingly

authoritative disparagement of it by cancer establishment sources. It

is this " condemnation " of hydrazine sulfate I wish to address—the

scientific gobbledygook of so-called studies, side effects,

carcinogenicity, toxicity, cautions, critiques and inferences woven

together by our cancer agencies' most talented " spin doctors " into a

web of outright misrepresentations, deception and scientific fraud.

(As an example of this fraud, NCI has posted an entry on the Internet,

" date last modified: 6/18/04, " stating " hydrazine sulfate has shown no

anticancer activity in randomized clinical trials, " which as will be

seen is patently untrue and does not reflect the ten years of

randomized clinical trials performed by Harbor-UCLA Medical Center

from 1981-1990 and the many published, peer-reviewed clinical studies

based on that body of work.)

 

The purpose of this statement is to guide you, step by step, through

the scientific development of hydrazine sulfate as an anticancer

agent, the clinical trials—and the high-level negative politics which

came to surround this drug from the very beginning. It will be plainly

seen that the cautions against this drug presented on the Internet by

our highest federal health agencies are but an assemblage of

misinformation and disinformation which acts to discourage this drug's

use both by individual patients as well as by well-meaning physicians.

 

First and foremost, it is important for you to know that, contrary to

implications made on the Internet, clinical trials of hydrazine

sulfate have been done and published in peer-reviewed medical journals

which circulate worldwide. And the truth is that every single,

informed-consent, controlled clinical trial of hydrazine sulfate,

performed in accordance with internationally accepted criteria and

standards of scientific conduct—without exception—has indicated

efficacy and safety of the drug. The only contrary results have been

the National Cancer Institute-sponsored trials of hydrazine sulfate in

which incompatible agents (medications) were used with the test drug.

It must be stressed that no legitimate researcher on this planet would

ever knowingly use an incompatible agent—or one even suspected of

incompatibility—in the trial of a test drug. Use of an incompatible

agent in a drug test, which acts to cause a negative study, can only

be the result of incompetence or deliberateness.

 

Secondly, Internet sources have implicated hydrazine sulfate to be

toxic or carcinogenic. Although hydrazine sulfate is

carcinogenic—i.e., can cause cancer—in some weanling mice given the

drug in their drinking water since birth, there has never been a case

of human cancer reported as a result of HS therapy . (In contrast,

routinely administered chemotherapy drugs are commonly

carcinogenic—and can produce up to 26% of " second cancers. " ) Perhaps

more importantly, the influential medical journal Annals of Internal

Medicine presented a " Brief Communication " (and accompanying

editorial) in its December 5, 2000 issue, of a single patient who

allegedly died of fatal hepatorenal failure as a result of " HS "

therapy. The only trouble was that no firm evidence was presented in

this paper that the patient in question ever took hydrazine sulfate.

The authors of this article stated: " We could not obtain samples of

the product he [the patient] ingested. " This means there was no

possibility of a direct examination of what it was the patient was

taking. The authors further stated: " His blood was not tested for the

presence of hydrazine. " But there are simple spectrofluorometric blood

tests that will confirm even the smallest residues of hydrazine

sulfate ingested even months earlier. It must be emphasized that no

medical journal on earth—of high repute or not—would publish an

article and editorial based on one case, calling attention of the

medical profession and public to the potential toxicity of a drug

gaining in common usage, without incontrovertible, verifiable,

air-tight evidence that the patient in question ever took the drug in

the first place. No journal would have the ethical recklessness to

disseminate an article having far-reaching public health consequences,

without absolute proof of its basic assumptions. But the editors and

writers of the Annals—with our federal health agencies' knowledge and

participation—chose to disseminate their reports to the media of the

world, to the medical profession of every country and to the Internet,

where the public would be sure to find them. To put this situation in

its proper context: While Annals chose to issue a " drug warning " based

on one, single presumptive case of fatal toxicity of HS in the 30

years since the drug has been in use, there are tens of thousands of

authenticated chemotherapy deaths each year . Has the Annals, or other

medical journals, or our federal health agencies, or the prominent

private-sector cancer organizations ever let the public know this?

 

Your life or the life of a loved one or friend may depend on your

reading, and understanding, the statement below. References are used

in support of the events, happenings and details of this expanded

statement.

 

Scientific Background. Hydrazine sulfate (HS), an inexpensive,

mass-produced chemical compound used for many industrial applications,

was first proposed as an anticachexia agent based on its inhibition of

the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEP

CK).1,2 It was further proposed that if tumor energy (ATP) gain and

host energy loss (resulting from cancer-induced excessive

gluconeogenesis) were functionally interrelated—as seemed probable—HS

could also, by indirect and non-toxic means, inhibit tumor growth

itself.3 Early in-vivo studies demonstrated that HS could inhibit

weight loss (cachexia) and tumor growth in a variety of transplanted

mouse and rat models, without direct cytotoxicity,2-6 could add to the

antitumor effects of chemotherapy drugs,7-9 and was free of

significant side effects.10 These results strongly suggested HS as a

new means of non-toxic cancer chemotherapy.11,12

 

Adverse Politics Begin. Despite this drug's early promise, from the

very beginning of clinical trials, HS was to be met with controversy

as a function of government action. On March 8, 1976, veteran

congressman James M. Hanley (Chair of the Post Office and Civil

Service Committee and a member of many committees and subcommittees)

requested a " status report " on HS from the director of the National

Cancer Institute, our country's—and the world's—largest and most

influential cancer agency. Within two weeks he received a reply which

stated: " Hydrazine sulfate has been tested in the Soviet Union at the

Petrov Institute in Leningrad [st. Petersburg ]. In a clinical study

directed by Dr. Michael Gershanovich, no evidence of meaningful

anticancer activity was reported. This information was communicated to

the NCI under the Joint U.S.-U.S.S.R. Health Agreement of 1972. " 13,14

Days later, however, reprints of the actual study became available.

Its English summary stated:

 

" Clinical observations enabled us to state a definite

therapeutic effect of hydrazine sulfate in patients with

lymphogranulomatosis [Hodgkin's and non-Hodgkin's lymphomas] and

malignant tumors of various localizations, when other measures of

specific therapy failed. " 15

 

This was exactly opposite of what was communicated to Congressman

Hanley. In fact, the text stated that because of the highly positive

findings the study was being immediately enlarged. As to whether the

NCI response to Congressman Hanley represented an innocent error on

the part of the NCI or a deliberate fabrication, a further letter from

the NCI, dated June 22, 1976, stated: " An abstract [summary] of the

Gershanovich study appeared in Cancer Therapy Abstracts (Vol. 16: No.

4 [19]75-2046), a journal published under contract to the NCI. " 16 This

published abstract antedated the NCI's response to Congressman Hanley

by six months. Thus, at the time the NCI was writing to Congressman

Hanley that the Soviet data were negative, the NCI already knew these

data were positive.

 

Early Clinical Studies. In 1975 three articles would appear in the

medical literature, detailing initial clinical results with hydrazine

sulfate. The first, the Soviet study,15 a phase II controlled clinical

trial, set forth astonishing results in a class of patients termed

" factually terminal [stage 4], " who had become unresponsive, or had

failed to respond initially, to conventional therapy: 58 percent

demonstrated anticachexia response (weight gain, performance status

improvement, normalization of the laboratory indices, etc.), and 35

percent showed antitumor response (tumor regression or stabilization);

one year later the initial series of 48 patients was enlarged to 95

patients, with essentially the same results.17 The second, a

pharmaceutical-sponsored IND (Investigational New Drug) study of 84

terminal and preterminal patients with different types of cancer

demonstrated a 59 percent anticachexia response and a 17 percent

antitumor response.18 The third, a small study of 29 patients

conducted at Memorial Sloan-Kettering Cancer Center, totally

uncontrolled for patient selection, drug dosage and treatment

schedule, and prior and concurrent therapy, found no long-term

improvements (although transient response was recorded).19 On the

basis of this totally uncontrolled MSKCC trial of 29 patients the

American Cancer Society, in March 1976, placed HS on its " Unproven

Methods " list.20 The ACS stated: " After careful study of the

literature and other available information, the American Cancer

Society does not have evidence that Hydrazine Sulfate is of any

objective benefit in the treatment of cancer in human beings. " In its

article, the ACS referenced only the uncontrolled MSKCC study, but

failed to reference the phase II controlled Soviet trial or the

(American) pharmaceutical-sponsored IND study. (In late 1979 the ACS

removed HS from its Unproven Methods list, in the wake of increasingly

positive data on HS.21)

 

In March 1979 the Soviet study was enlarged to 225 patients. Published

as an abstract in the March 1979 Proceedings of the American

Association for Cancer Research, controlled for patient selection and

prognosis, performance status, dosage protocol, prior and concurrent

therapy, the study reported overall results of 65 percent anticachexia

response and 44 percent antitumor response. Anticachexia response was

described as " appreciable improvement of appetite and general status,

disappearance or reduction of severe weakness characteristic of the

pretreatment period, reduction or complete elimination of pain,

tendency toward normalization of the laboratory findings " ; antitumor

response included tumor regression ( " less than 25 to greater than 50%

of initial tumor volume " ) and tumor stabilization (from " 3-6 months " );

side effects included " minimal nausea, dizziness, anorexia,

polyneuritis (1.7%) [tingling of the fingers] " —and the absence of bone

marrow depression ( " leukopenia and thrombocytopenia were not

observed " ). In this class of patients no efficacy and safety findings

approaching these had ever before been reported. Nevertheless,

although arrangements had been made through the Soviet and American

governments to have Dr. Gershanovich come to this country to discuss

these results, after traveling more than 7,000 miles he was not

permitted to present his paper orally at the annual scientific

meetings of the American Association for Cancer Research in New

Orleans . Asked by the media at this conference whether " consideration

should not have been given to the fact that [this] Russian trial was

the first large-scale study of [HS], purporting to show significant

benefits from its use " —and therefore become subject to open discussion

by the world oncology community—the program chairman of the AACR

stated: " The Gershanovich paper is not going to be presented, and

that's it. " 22 (In 1981 the Gershanovich data were published as a

full-length paper in the American peer-reviewed journal, Nutrition and

Cancer.23)

 

Also in 1979 a negative paper on HS of 25 non-randomized, non-blinded,

non-controlled, open-study patients would be published in the journal

Cancer Chemotherapy and Pharmacology,24 whose editor-in-chief was an

NCI official, authored by Dr. William Regelson (now deceased) and

colleagues from the Medical College of Virginia. In this totally

unaudited study, 7 of the " negative " patients died (of their disease,

not from the drug) within 11 days of starting HS therapy (1 died on

the very first day), another was " lost to follow-up " after two weeks,

2 others received prior chemotherapy which had not yet cleared, 1

received concurrent medication shown to be incompatible with HS as

long as four years previously,8,15,25 and 16 received HS less than the

required four-week minimum (l patient received HS for only 1 day, 9

for 1 week or less, 16 for 2 weeks or less). Of the 25 " negative "

patients only five could qualify for evaluation according to

established drug-testing protocol. Because only 20 percent of the

patients of the study were evaluable, it is unclear how this paper

achieved publication, since it was apparent that it could not have

been subject to normal, independent peer-review procedures.

 

The American Medical Association Enters The Fray. In January 1980 the

Commentary section of the Journal of the American Medical

Association26 would present another negative article on HS, again

authored by Dr. Regelson. The JAMA was at the time perhaps the most

authoritative medical journal in the world and its prestigious

Commentary section, located at the beginning of many issues, was in

effect a forum that usually addressed an important social or political

medical problem or question—and was thus a reflection of the views of

organized medicine at its highest levels. In this Commentary article

Dr. Regelson stated that he and " others " had performed randomized,

double-blind studies on HS that were negative. ( " In both randomized

double-blind and nonrandomized studies, our group and others have

tested hydrazine sulfate in advanced cancer patients…. " ) But the truth

was that Dr. Regelson—or " others " — never performed any double-blind

studies and indeed the only study that Dr. Regelson ever performed was

the one, previously discussed, in which 80 percent of the patients

were unevaluable and which could not have been published on the basis

of independent peer-review. In fact Dr. Regelson never once mentioned

the Gershanovich results—the only truly controlled (phase II) clinical

trial of HS up to that time (1979), which dwarfed all other studies

(225/233 evaluable patients) of HS combined. (Gershanovich's name did

not appear once in the text.) Of HS Dr. Regelson only stated:

" [Hydrazine sulfate] does inhibit the Walker 256 carcinoma [a rat

tumor] and has shown synergy with chemotherapy in the L 1210 in

mice….Where does that leave us? " Thus extolling the " double-blind "

studies he had never published or performed, and omitting any mention

of the large-scale, positive, controlled Russian trials that had been

published and performed—Dr. Regelson's Commentary article sent an

unmistakable message that HS was tantamount to quackery medicine, in

effect regarded by the cancer establishment (he referred to himself as

" we members of the Establishment " ) as a pharmaceutica-non-grata .

Equally disconcerting was the fact that the editorial staff of the

JAMA had apparently not checked to ascertain that Dr. Regelson—or

" others " —had indeed published double-blind studies on HS, in effect

that what Dr. Regelson was writing was in fact true. JAMA 's failure

to perform this most elementary task served only to reinforce Dr.

Regelson's egregiously erroneous " message " to the practitioners of

American medicine.

 

Randomized Clinical Trials. In 1981 the American Cancer Society began

sponsorship of prospectively randomized, double-blind,

placebo-controlled clinical trials of HS at Harbor-UCLA Medical Center

under the distinguished leadership of well known cancer investigators

Drs. Jerome B. Block and Rowan T. Chlebowski. (RCTs are considered the

" gold standard " of clinical testing, since they tend to minimize bias

from all sources.) In February 1984 these investigators reported27 in

the respected journal Cancer Research that in a series of 38 patients

with widespread lung, colon, breast, throat and other cancers, HS

reversed abnormal carbohydrate metabolism associated with cancer

cachexia. This represented a watershed work, in that for the first

time it was demonstrated (under double-blind, placebo-controlled

circumstances) that alteration of abnormal host metabolism could

result in measurable clinical benefits, including weight improvement

and stabilization, potentially opening the door to a new type of

cancer therapy.

 

Thus by the middle 1980s dual scientific horizons—the Soviets and

Harbor-UCLA Medical Center—had emerged, independently corroborating

one-another's clinical results on HS, the strong preponderance of data

indicating this drug to represent a promising new therapeutic agent.

 

Politics Deepen . First published in the early 1980s, one of the most

influential cancer textbooks in the world was (and still is) CANCER,

Principles & Practice of Oncology, whose principal editor was Dr.

Vincent T. DeVita, Jr., then director of the NCI. In its first edition

in 1983 this textbook carried a chapter, " Unproven Methods of Cancer

Treatment, " authored by Dr. Jane E. Henney, deputy director of the NCI

(who would become Commissioner of the Food and Drug Administration in

1998). As expected, Dr. Henney's chapter would not include HS, since

this drug had been removed from the American Cancer Society's Unproven

List three years previously and the Soviet phase II study of 225

patients had already been published in 1981 in the American

peer-reviewed journal, Nutrition and Cancer.23 But in this textbook's

second edition, published in 1985,28 in the wake of further positive

clinical studies, Dr. Henney's chapter, strangely enough, did include

HS. By that time the Russian (Soviet) series had been enlarged to 356

patients,29 reporting essentially the same highly positive results as

in earlier papers, again in very late stage, refractory patients. In

her chapter, Dr. Henney characterized these Soviet results—in this

instance 44 percent antitumor response and 50 percent anticachexia

response, previously unheard of in this class of patients—as merely

showing " hints of subjective activity. " And although the watershed

February 1984 Cancer Research Harbor-UCLA article—and its predecessor

ASCO abstracts of 198230 and 198331 —were available to her before the

chapter went to press (in her chapter Dr. Henney quoted a reference

dated April 1984), no mention whatsoever was made of the Harbor-UCLA work.

 

In subsequent editions of the DeVita textbook Dr. Henney's chapter was

entirely removed. Nevertheless, a signal was sent to the oncology

world that the two highest officials of the NCI—Drs. DeVita and

Henney—had seen fit to characterize HS as an " unproven method " at a

time when positive data, including randomized, double-blind,

placebo-controlled studies, were emergent from unimpeachable clinical

sources.

 

Harbor-UCLA Grant Application To The NCI . On July 1, 1983

Harbor-UCLA, under the principal investigatorship of Rowan T.

Chlebowski, M.D., Ph.D., considered one of this country's leading

authorities in intermediary cancer metabolism, submitted a grant

application to the NCI to continue its successful, initial studies

with HS and extend this salient work with the performance of an

all-important clinical outcome study. Over the next few years NCI

action would prove disconcerting to the Harbor-UCLA investigators.

When Chlebowski and his colleagues made changes in the application

recommended by the NCI study section, NCI referred the revised grant

application to new and sequentially different study sections, which

knew less and less about it and would demand further changes, until

action by a third study section—submission to three, successive study

sections had never before happened to any NCI grant application—would

demand changes that had nothing to do with the original grant

application or with changes recommended by the first, and primary,

study section. In 1985 Dr. Chlebowski received notice from the NCI

that his grant application had been approved but achieved only a

" borderline " funding score, indicating a substantial uncertainty it

would be funded. Chlebowski therefore sent an urgent letter to the

NCI,32 requesting " special funding consideration. "

 

In his letter Dr. Chlebowski, stated: " Our cumulative data are largely

in agreement with the over 300 patient Russian experience where

clinical benefit was observed in approximately half the patients

receiving hydrazine sulfate therapy. " Emphasizing the importance of

his research, he stated: " If the negative prognostic implications of

weight loss in these cancer patient populations could be overcome by

hydrazine sulfate—[which he termed " representative of an entirely new

class of therapeutic compounds " ]—a major therapeutic advance

applicable to hundreds of thousands of cancer patients would be achieved. "

 

Chlebowski received no reply to his letter in over a month. A copy of

his letter was then forwarded to the direct attention of Margaret

Heckler, Secretary of Health and Human Services, for an " unbiased

review of the hydrazine sulfate situation and of Dr.Chlebowski's

letter in particular. " 33 Two months later Dr. Chlebowski received a

" Notice of Grant Award " from the NCI for his three-year project,

" Glucose Metabolism and Hydrazine in Cancer Cachexia, " to begin

September 1, 1985.

 

In 1987 three papers were published as a result of this new (and

residual ACS) funding. In February34 Chlebowski and colleagues would

demonstrate, in a full-length paper, that weight maintenance in

HS-treated patients was statistically associated with an increase in

the effectiveness of calories ingested, that the mean blood

circulatory levels of HS nine hours following a standard oral dose (60

mg) ranged from 0 to 89 ng/ml—average: 45± 16 ng/ml—implying that

patients who received no benefit from HS may not be absorbing it from

their gastrointestinal tracts (i.e., patients with near-zero blood

levels), that side effects were minimal, consisting of low levels of

nausea, lightheadedness and " less than 1% " peripheral neuritis. In

August35 Harbor-UCLA investigators, again in a full-length paper,

demonstrated that HS reduced protein breakdown and preserved

peripheral (body) muscle mass in patients with late stage

non-small-cell lung cancer (NSCLC); it was also found that HS acted to

maintain serum albumin levels , an important prognosticator of

survival in these patients.

 

However, in 1987,36 it would be a third paper published only in

abstract form by the Harbor-UCLA investigators which would prove to be

most consequential. In this abstract (and in an oral presentation at

the annual scientific meetings of the American Society of Clinical

Oncology that year) substantive evidence was presented that HS

resulted in statistically increased survival in a subset of early

patients with NSCLC, which had never before been reported as a result

of drug therapy: HS addition to standard chemotherapy resulted in a

median survival time of 328 days, vs. placebo addition to standard

chemotherapy which resulted in a median survival time of 209 days, the

difference being statistically significant to the p<.05 level. It was

the first time that a treatment directed primarily at abnormal host

metabolism was demonstrated to favorably influence survival outcome in

patients with malignant disease.

 

By the beginning of 1988, prospectively randomized, double-blind,

placebo-controlled studies had thus indicated that HS: (a) normalized

abnormal glucose metabolism, (b) resulted in increased effectiveness

of ingested calories, © caused weight gain or weight stabilization,

(d) reversed protein breakdown and muscle wasting, (e) maintained

serum albumin levels, and (f) resulted in statistically significant

survival increase in lung cancer patients. However, that same year

NCI's Dr. DeVita, representing this country's cancer leadership at its

highest levels, would pronounce HS a " ho-hum idea, " referring to this

drug as merely " a therapy that gave you plumper people by the time

they died " 37 (and reaffirming his statement made to the media in 198l:

" We throw away drugs that are better than hydrazine sulfate " 38).

 

Multi-Institutional Grant Application to the NCI. Recognizing the

large therapeutic potential of HS as a result of their metabolic and

clinical outcome studies, Harbor-UCLA investigators undertook to

enlarge their work from a single-institutional study to a multicentric

study and from examination of a single tumor type, namely lung, to

three tumor types: lung, breast and colon. The institutions involved

would be: Harbor-UCLA Medical Center (study headquarters), Emory

University Medical Center, University of Toronto Cancer Center,

Memorial Sloan-Kettering Cancer Center and M. D. Anderson Hospital and

Tumor Institute. Among the co-principal investigators were some of the

most distinguished names in cancer medicine and research: Dr. Dan

Nixon, Dr. Murray Brennan, Dr. G. G. Boyd, and others. Dr. Chlebowski,

a most experienced—and successful—grant writer, undertook to write the

initial draft of the multi-institutional grant application, then sent

it to his colleagues at the cooperating institutions for their

comments, then revised it according to their recommendations. At about

the time of publication of the Harbor-UCLA outcome study abstract

(1987), Chlebowski sent the completed multicentric grant application

to the NCI. Chlebowski, considered a " luminary " in the field of cancer

metabolism investigation (he was one of thirteen scientists selected

by the U.S. government to help establish a cancer treatment and

teaching center in Taipei, Taiwan39 ), was shocked some months later

to receive notification from the NCI that his grant application was

not only not approved, but received one of the worst scores possible

(at the time a perfect score was `1, " the worst " 500 " : the number

given to his application was 460). In giving Chlebowski's multicentric

application—written in conjunction with some of the country's top

research institutes and scientists—such a resoundingly high (poor)

score, the NCI in effect gave indication of its apparent displeasure

with further, independent trials of HS. Shortly thereafter, NCI—the

frequent and assertive adversary of HS since 1976—assumed sole control

of all further clinical testing of this agent.

 

Hired-Gun Editorial. But the Harbor-UCLA investigators, and HS, would

be dealt another surprise at the hands of the cancer establishment. In

early 1988, after gathering and collating all the data from its

outcome study, Harbor-UCLA sought to publish a full-length paper on

this study, detailing all study parameters—including patient

selection, concurrent medication, treatment protocols, methods of

study conduct, statistical analyses, etc.—in a journal of unquestioned

reputation. Anticipating no difficulty in this task, Chlebowski and

his co-workers sent this paper off to a mainstream, well regarded,

internationally circulated cancer journal, in which they had published

many times previously. This journal's editorial board kept his paper

for four months—instead of the usual six weeks—and then rejected it.

He then submitted the paper to the Journal of Clinical Oncology —a

journal of the American Society of Clinical Oncology —considered by

many as the emergent, authoritative journal for clinical studies of

cancer drugs. In early 1989 the JCO agreed to publish the Harbor-UCLA

paper, with " major revisions, " most of which related to methodology

and details of statistical analyses. However, each time Harbor-UCLA

submitted its revisions, the JCO would ask for further changes.

Finally, in June 1989 Harbor-UCLA received final acceptance by the

JCO, stating its paper would be published in the journal's January

1990 issue.

But it would not be a " normal " publication. Ordinarily a journal

submits to the author(s) galley proofs (page proofs) of the paper

shortly before publication. These proofs are strictly of the

author(s)' article and are for the express purpose of making last

minute changes, additions or corrections. No galleys or proofs of any

other articles or content appearing in the journal issue are ever sent

to the author(s)—which would be considered highly unethical. But when

Chlebowski and his group received galleys of their article, included

in these galleys were the galleys of yet another paper—an editorial,

" Hazards of Small Clinical Trials, " taking aim exclusively at the

Chlebowski paper and the conclusions reached. Up to this time no

journal had ever sought to attack its own lead article. Confronted

with the choice of withdrawing their paper with the understanding that

the editorial, too, would be withdrawn,40 Chlebowski and his group

chose rather to go ahead with publication.

 

Although in the January 1990 issue of the JCO Chlebowski and his group

were able to demonstrate unequivocally that HS addition to

chemotherapy significantly extended the lives of NSCLC patients,41 the

effect of the editorial (which preceded the Chlebowski paper)42 was

devastating. Written by Dr. Steven Piantadosi of the Johns Hopkins

Oncology Center (who at the time was also a member of FDA's Oncology

Drug Advisory Committee which recommended to the FDA which cancer

drugs to approve and which not to approve), the editorial singled out

only the HS results, shredding the Harbor-UCLA work on the basis that

it was " too small " a clinical study to be valid. However—and as

pointed out in a subsequent issue of the JCO43—the Chlebowski trial

was comprised of 65 patients, considered adequate for any phase III

single-institution trial, whereas in the same journal issue there were

trials of 15, 23, 24, 29, 30, 31, 40, 40, 43, 49, and 51 patients, and

the editorial took issue with none of these or the conclusions

reached. The effect of this " hired-gun " editorial was to dramatically

curtail the use of HS in the U.S., and cast a pall over future,

independent clinical research with HS, discouraging individual

researchers and their sponsoring institutions from implementing any

such undertakings.

 

(In contrast, in 1990—the same year as the Piantadosi editorial—HS,

following approval for use throughout the Soviet Union, was named

Sehydrin by the nomenclature commission of the U.S.S.R. Ministry of

Health and, one year later, approved by the Pharmacology Committee of

the Ministry of Health of Russia [the equivalent of the U.S. Food and

Drug Administration] for general oncology use.)

 

The NCI-Sponsored Studies. In 1988 the NCI announced it would sponsor

three large-scale multicentric (multi-institutional) phase III studies

of HS, the first (and largest) of which would be conducted under the

auspices of the Cancer and Leukemia Group B (CALGB) Cooperative

Oncology Group of the NCI, headquartered at the Scripps Clinic in La

Jolla . The second and third were conducted by the North Central

Cancer Treatment Group (NCCTG) headquartered at the Mayo Clinic. NCI's

Cancer Therapy Evaluation Program (CTEP), headed by Dr. Michael

Friedman, held the portfolio of the planned HS studies.

 

HS is an irreversible and potent MAO (monoamine oxidase) inhibitor, a

class of compounds that can have potentially deadly interactions with

other drugs. For over three decades it has been known that central

nervous system depressants—such as barbiturates, tranquilizers and

alcohol—are incompatible with MAO inhibitors and use of the two

together could result in extremely dangerous effects.44 Because these

agents—especially tranquilizers—were commonly used as supportive

agents in cancer patients, CTEP and all study chairs of the planned

NCI-sponsored studies were alerted that use of HS in conjunction with

these agents would constitute a clinical hazard,45-47 were advised

that these supportive agents should be excluded in any study of HS (if

not, a negative study would result), and were provided published and

unpublished data8,15,26,48,49 indicating deleterious interactions

between the two. (For example, one of the provided studies indicated

that tumor bearing rats given either a benzodiazepine tranquilizer or

HS suffered no harmful effects, whereas when the two types of

compounds were given together in the same doses, the rats became

comatose and a 50% to 60% mortality resulted, depending on which

benzodiazepine was given.) CALGB's reply was that after careful review

and discussion, " barbiturates, tranquilizers and alcohol will not be

specifically excluded. " 50

 

In the June 1994 issue of the JCO, the three NCI-sponsored studies

were reported as negative.5l-53 Publication of these studies was

apparently carefully planned, since they appeared consecutively —even

though they were finished at far different intervals (February 1991,

October l992, November 1992). The first (CALGB) study was finished a

year and a half before the last studies—and held until the last

studies were completed, the effect of which was that their

simultaneous—and sequential —publication might have greater impact. In

the largest of these studies it was emphasized that " no patients

received barbiturates and virtually no patients received

phenothiazine-type tranquilizers with the exception of

prochlorperazine (Compazine), which was used as a short-term

anti-emetic [anti-nausea] agent. " No mention was made of use of the

more powerful benzodiazepine tranquilizers, the implication being that

the benzodiazepine tranquilizers were not used. Tranquilizers were

thus indicated as used only sparingly and for very short periods of

time. Yet another—fourth—article on HS54 appeared in the same journal

issue, an editorial identifying HS as a " vampire " and the

NCI-sponsored studies as " three stakes in the heart of hydrazine sulfate. "

 

The GAO Investigation. Because of evidence of irregularities presented

to Congress, the ranking members of the Subcommittee on Human

Resources and Intergovernmental Relations of the House Government

Operations Committee ordered a General Accounting Office investigation

of the NCI-sponsored HS studies (the GAO is the investigative arm of

Congress). This investigation was commenced in June 1994 under the

leadership and direction of 28-year veteran investigator Barry D.

Tice, Assistant Director of the GAO, Health Planning Division. The GAO

soon learned that far from the exclusion of barbiturates and

short-term use of only Compazine as a tranquilizer, the CALGB study

included widespread—and in many cases prolonged—use of a spectrum of

both phenothiazine tranquilizers as well as the more powerful

benzodiazepine tranquilizers, with no exclusion of barbiturates or

restriction on use of alcohol. Among the phenothiazine tranquilizers

used were: chlorpromazine, perphenazine, prochlorperazine and

triethylperazine; among the benzodiazepine tranquilizers were:

alprazolam, clorazepate, diazepam, flurazepam, lorazepam, midazolam,

oxazepam, temazepam and triazolam; barbiturates included:

pentobarbital, phenobarbital, secobarbital and donnatal. These are

among the most powerful depressants known, with such trade names as

Thorazine, Compazine, Xanax, Valium, Dalmane, Ativan, Restoril,

Halcion, Nembutal and Seconal. They are all incompatible—and

potentially dangerous—with MAO inhibitors. It was ascertained that

many patients in these studies received both phenothiazines and

benzodiazepines, and some more than one tranquilizer at a time. As a

consequence the CALGB was forced to publish a new paper clarifying the

use of these agents. The new paper55 specified that 94% of all

patients received tranquilizers, half receiving the main

benzodiazepine tranquilizer used, lorazepam (Ativan), on a long-term

(>48 hours) basis, that the data were not computerized and that

information regarding the use of concomitant medications " was not

complete. " At the end of this new paper the authors nevertheless

maintained: " The correction and clarifications offered here do not

change the conclusions originally reported from our study. "

 

The principal question of this investigation was whether or not HS was

an MAO inhibitor. If so, the NCI-sponsored studies would be, by

definition, intrinsically flawed (since tranquilizers were known to be

incompatible with MAO inhibitors). Despite pharmacology textbooks

identifying hydrazine as an irreversible MAO inhibitor over the past

30 years, the NCI vigorously denied to GAO investigators that HS was

an MAO inhibitor. On September 14, 1994 Dr. Michael Friedman,

associate director of CTEP and in charge of NCI's HS studies, wrote to

Dr. Vera A. Gorbunova inquiring whether " Russian oncologists restrict

the coadministration of hydrazine with alcohol, antiemetics,

tranquilizers and barbiturates. " 56 Within three weeks he received a

reply from Russian oncologist Dr. M. B. Bychkof: " Hydrazine sulfate is

a modulator of biologic reactions…it functions as an inhibitor of

monoamine oxidase [MAO] and therefore cannot be used in combination

with alcohol, tranquilizers and barbiturates. " 57 Nevertheless Dr.

Friedman would later write to Barry Tice: " That hydrazine sulfate is

an MAO inhibitor seems unsupported by our review of the data. " 58

 

Repeatedly asserting that HS was not an MAO inhibitor—acknowledgment

by NCI of MAO inhibition by HS would be tantamount to an admission

that NCI wittingly or unwittingly used known incompatible agents

( " negative bias factors " ) in its HS studies—and leaving GAO

investigators confused59—NCI submitted to the GAO60 a series of nine

" retrospective analyses " alleging that even if there were an

incompatibility between HS and alcohol, tranquilizers and

barbiturates, usage of these substances made no difference anyway to

the studies' outcome. But these retrospective analyses were filled

with statistical irrationalities and subjected to an outside,

independent audit by consultant biostatistician Richard D. Wilkins, a

former senior biostatistician at a major pharmaceutical company. In

his 19-page report, Wilkins summarizes: " The NCI retrospective

analyses, as presented, cannot statistically substantiate any claim

that the use of adjunctive tranquilizers and/or barbiturates had no

(deleterious) effect on hydrazine sulfate drug action or on survival

outcome. " 61

 

On June 5, 1995 the GAO issued its 28-page Final Draft Report62 of its

ten-month investigation which was, in effect, a scathing criticism of

the NCI-sponsored studies, which GAO investigators stated actually

contributed to, rather than clarified, the controversy surrounding HS.

Its title was: " NIH Actions Spur Continued Controversy Over Hydrazine

Sulfate Therapy. " The report stated: " NCI did not conduct adequate

oversight of these trials. It did not take sufficient measures to

appropriately address concerns over alleged incompatible agents….The

issue of possible incompatibility of hydrazine sulfate with certain

other agents is unsettled….The clinical importance of possible

interaction between hydrazine sulfate and tranquilizing agents,

barbiturates, or alcohol has not been determined and the issue remains

unsettled. " This was circulated as a perfunctory courtesy to the Food

and Drug Administration, the NCI, the Public Health Service and

" interested congressional committees " before publication as an

official document. Two days later, as set forth in a published

investigative article, NCI representatives met with GAO, expressing

" grave concern " lest the Draft Report be made public, and five days

later presented GAO with an 8-page memorandum " demand[ing] a major

rewrite. " 63 Shortly thereafter Barry Tice was removed from his

position as lead investigator and relieved of all responsibilities in

this case. Three months later (September 13, 1995) GAO published its

official—new—report of its investigation. The new title read:

" Contrary to Allegation, NIH Hydrazine Sulfate Studies Were Not Flawed. " 64

 

Tice commented, regarding the changes made in the Draft Report :

" There weren't that many words changed from our Final Draft Report,

but…the impact of the changes and few key deletions was tremendous.

Those changes took NCI almost completely off the hook….In my almost 30

years at GAO I was rarely forced to accept rewrites or deletions

that…significantly altered a report's message. " 63

 

Tice retired from his long career at GAO soon after the altered GAO

report was published. However, he was still haunted by the lingering

doubt as to whether HS was an MAO inhibitor, on which, he knew rested

the crux of the entire GAO investigation. As a private citizen, using

his own stationery, he wrote to Robert M. Julien, M.D., Ph.D., of St.

Vincent Hospital, Portland, Oregon, an acknowledged expert in the

field of drug interactions and author of the seventh edition of A

Primer of Drug Action65—whose book he had come across after leaving

GAO—asking whether HS was an MAO inhibitor.66 Tice received a timely

reply indicating HS was " an irreversible MAO inhibitor " 67 (Dr.

Julien's emphasis).

 

On October 25, 1999, four years after the NCI had so vigorously denied

to GAO investigators that HS could be an MAO inhibitor, lest the

NCI-sponsored studies be termed " intrinsically flawed " —four years

after the GAO investigation had safely passed—NCI issued a multipage

newsletter on complementary and alternative medicine, discussing HS.

Its opening line was: " Hydrazine sulfate is an MAO inhibitor…. " 68

 

The FDA. On May 7, 199969 FDA's Pharmacy Compounding Advisory

Committee (PCAC), convened under the stewardship of Dr. Jane E.

Henney, newly appointed Commissioner of the FDA (who as deputy

director of the NCI in 1985 included HS in her chapter28 on unproven

methods, at a time when positive, placebo-controlled, double-blind

data were reporting efficacy and safety of the drug)—met to consider,

among other questions, the de-listing of HS from the " bulk compounding

list. " If HS were de-listed, this drug would become virtually

unavailable in this country.

 

Because of excesses taken by the advisory committees (although these

committees were made up of non-FDA scientists and lay people, they

were nevertheless sympathetic to FDA concerns and frequently presented

only those viewpoints sanctioned by the FDA), Congress passed the

Federal Advisory Committee Act of January 26, 1998, which provided

that presentations made to the advisory committees be " fairly balanced

in terms of points of view presented " and that " the advice and

recommendations of the advisory committee will not be inappropriately

influenced by the appointing authority. " These two provisions were

simply meant to safeguard against one-sided presentations and/or actions.

 

In flagrant violation of the Federal Advisory Committee Act of January

26, 1998, the " appointing authority " (FDA's Center for Drug Evaluation

and Research), however, invited only those who could speak against HS

to its PCAC meeting of May 7, 1999. Three outspoken adversaries70,71

of HS gave testimony (in favor of de-listing) to the committee, one of

whom (charged with a " conflict of interest " in his role in the

NCI-sponsored HS studies72) was not present in person but gave

testimony by videotape and live telephone-hookup.

 

The appointing authority issued no invitations to any qualified

proponents of HS to give testimony, either in person or by videotape

or by live telephone-hookup, in favor of HS, and thereby balance the

" points of view presented, " as required by the Federal Advisory

Committee Act of 1998. As a result the committee—sustaining a virtual

blackout of information on the metabolic and clinical efficacy and

safety data of the drug as presented in the peer-reviewed

journals—voted unanimously, 12-0, to recommend the de-listing of HS

from the bulk compounding list.

 

On February 6, 2001, section 353a of the Food and Drug Modernization

Act of 1997, under which authority the PCAC voted its recommendation

of May 7, 1999 to de-list HS from the bulk compounding list, was

declared unconstitutional by a panel of three judges of the Ninth

Circuit Court of Appeals. The FDA thereupon petitioned this court for

a rehearing en banc (all 11 justices). The Court unanimously declined

to do so. FDA then took this matter to the U.S. Supreme Court, the

Justice Department arguing the FDA's case. On April 29, 2002 the

Supreme Court upheld the Ninth Circuit Court of Appeals, in effect

declaring section 353a—and all action taken under its authority

(including the recommended de-listing of HS)—null and void.

 

Academe Joins In . What could not be done to eliminate HS by official

intimidation, by rigged clinical trials, by GAO complicity with the

NCI, by one-sided PCAC (FDA) action, our cancer leadership sought to

accomplish by enlisting what can only be termed the academic whoredom

of one of this nation's premiere medical journals.

 

As alluded to previously, in its December 5, 2000 issue, the

influential medical journal, Annals of Internal Medicine, published a

" Brief Communication " and editorial73,74 alleging that HS caused fatal

hepatorenal (liver/kidney) toxicity in a single patient. There was one

thing " wrong, " however. No proof was presented that the patient ever

took HS. The authors stated: " We could not obtain samples of the

product he [the patient] ingested. " This meant there was no

possibility of a direct examination of what it was the patient was

taking. The authors further stated: " His blood was not tested for the

presence of hydrazine. " But there are simple blood tests that will

detect even the smallest traces of the drug ingested months earlier.

It must be emphasized that no medical journal anywhere—of high repute

or not—would publish an article and editorial based on one case,

calling attention of the medical profession and public to the

potential toxicity of a drug gaining in common usage, without

incontrovertible, verifiable, air-tight evidence that the patient ever

took the drug in the first place. No journal would have the ethical

recklessness to disseminate an article having far-reaching public

health consequences without absolute proof of its basic assumptions.

In this regard the authors wrote: " It is not necessary to be certain

that a direct cause-and-effect relationship exist between the product

and the adverse clinical event…to file a [toxicity] report [to the

FDA]. " The authors were in effect stating that it was not necessary to

know for sure that HS caused the adverse clinical event before

reporting it to the FDA. The authors then stated: " This report [the

article and editorial] suggests but does not prove that hydrazine

sulfate caused the liver and kidney failure. " Thus, knowing full well

that its position was unsubstantiated, the Annals, one of this

nation's top medical journals, went ahead anyway, disseminating its

" drug alert " to doctors worldwide, across the Internet and onto the

front pages of newspapers everywhere—without consideration to the

heavy price that large numbers of cancer patients, their families and

loves ones would pay if its message were incorrect.

 

To understand the moral turpitude of the Annals' action, it is

necessary to know that—in contrast to the single, reported,

presumptive case of fatal HS toxicity (in the drug's 30 years of

use)—there are tens of thousands of authenticated chemotherapy

fatalities, deaths from chemotherapy drugs, in this country each year

.. Has the Annals, or other medical journals, or our federal health

agencies, or the prominent private-sector cancer agencies ever let the

public know this?

 

AIDS And Hydrazine Sulfate . The two major causes of death ( " risk

factors " ) in AIDS patients are weight loss and viral (HIV)

replication. In 1987 Harbor-UCLA Medical Center received a grant from

the U.S. National Institute for Arthritis and Infectious Diseases

(NIH) to study HS in the treatment of AIDS patients with Kaposi's

sarcoma. Prior metabolic studies of AIDS patients by Harbor-UCLA had

revealed that weight loss was dependent on serum albumin levels, such

that: patients with serum albumin levels equal to or greater than 3.5

g/dL survived more than 730 days from diagnosis; patients with serum

albumin levels less than 3.5 g/dL survived 103 days; and patients with

serum albumin levels equal to or less than 2.5 g/dL survived only 17

days.75 Since HS had been demonstrated to result in serum albumin

maintenance and weight gain in late stage cancer paitents,41 it was

reasoned that this treatment might result in similar metabolic effects

in AIDS patients, with the consequence of reversal of disease and/or

prognosis.

 

Although the Harbor-UCLA grant was funded and preparations for the

study, including patient accrual, had been in progress, the study was

never commenced and study funds were returned to the National

Institute for Arthritis and Infectious Diseases.

 

The reason for this action was attributed to the ongoing HS controversy.

 

Fueling The Current Controversy. The present controversy surrounding

HS is sustained by two " arms. " The first is the " difference of

opinion " generated by the NCI-sponsored, negative HS studies, in

contradistinction to the long-term, positive studies of Harbor-UCLA

Medical Center and those headquartered at the Petrov Research

Institute of Oncology. But the NCI-sponsored studies of HS—a potent

and irreversible MAO inhibitor— were carried out in the presence of

incompatible agents. The fact is that " every…informed-consent,

controlled clinical trial of hydrazine sulfate—with the exception of

the NCI-sponsored studies, confounded by the long-term…use of agents

known to be incompatible with MAO inhibitors—has demonstrated efficacy

and safety of the drug. " 76 It must be stressed that use of

incompatible agents in a drug trial—or those even suspected of

incompatibility—is essentially unknown and violates all accepted

international principles of drug testing. Thus, no matter what

credentials NCI brings to its sponsored studies—no matter how

strenuous its voice to the contrary—the NCI studies are scientifically

invalid . Use of an incompatible agent in a drug test in effect

violates every precept of study conduct known to science. Nor can the

NCI assert that the GAO validated its study conclusions. The Final

Draft Report of the ten-month GAO investigation, altered at the last

moment, showed the NCI-sponsored studies to be inconclusive, to in

fact spur on the HS controversy; its lead—30-year veteran—investigator

was relieved of all further responsibility in this investigation; and

the GAO report was changed dramatically in support of the

NCI-sponsored studies. The changes made " took NCI almost completely

off the hook… " according to the lead investigator, Assistant Director

of the GAO, Health Planning Division, Barry D. Tice.63

 

The second " arm " sustaining the HS controversy is comprised of

economic factors. Unlike most chemotherapy—and anti-AIDS—drugs which

are costly, HS is almost without expense. Fine biochemical companies

manufacture HS in essentially two grades: technical—lower purity, and

reagent—99+% purity, which is considered drug quality. The listed

(catalog) cost for reagent grade—drug quality—HS is only

three-quarters of one cent per average human dose (60 mg) administered

to a cancer patient. A front-page story from the Sunday, January 26,

2003, New York Times ( " Drug Sales Bring Huge Profits, and Scrutiny, to

Cancer Doctors " ) indicates that " cancer doctors are pocketing hundreds

of millions of dollars each year by selling drugs to

patients….Oncologists can make huge sums—often the majority of their

practice revenue—from the difference between what they pay for the

drugs [they administer] and what they charge insurers and government

programs….oncologists in private practice will typically make

two-thirds of their practice revenue from [this] chemotherapy

concession. " 77 Given the extreme inexpense of HS, oncologists are not

going to make " the majority of their practice revenue, " buying HS at

such low prices and reselling it to patients, insurers and government

programs, no matter how high the mark-ups. HS thus represents a

formidable economic challenge to oncologists, for cancer doctors and

those who administrate and direct our cancer programs are well aware

that this drug's routine use may significantly reduce not only

oncology funding and practice income but may also threaten the fiscal

machinery of cancer centers, cancer hospitals, cancer treatment,

cancer care, cancer research, cancer administration and cancer

pharmaceuticals.

 

The Toll. More than 1.2 million new cases of cancer are reported in

the U.S. each year; more than 600,000 Americans die from this disease

annually. The Petrov (Russian) data, corroborated by the Harbor-UCLA

data,32,78 indicate that of every million late stage cancer patients

treated with HS, more than half a million would receive measurable

symptomatic improvement, 400,000 would have their tumors cease growing

or regress, and some would go on to long term survival.

 

If these data are correct—as seems likely—the human toll, in terms of

needless suffering and/or premature death, because of a lack of access

to HS therapy, has been 5 million persons in the last 10 years in the

U.S. alone, many more worldwide.

 

The National Cancer Institute and the Food and Drug Administration, as

well as private-sector cohorts, are principally responsible for this

woeful public health calamity. Their sham message to the public—of

" validity " of the flawed NCI-sponsored studies, of potentially fatal

" toxicity " of HS, of " validation " by the GAO of the NCI study

results—has served to deceitfully undermine use of what appropriately

controlled clinical trials have demonstrated to be a safe and

effective drug and, in so doing, impose a public health menace on

significant numbers of cancer patients worldwide.

 

Concluding Remark . The NCI and FDA have the capacity to reverse the

present situation with HS. The new leadership of these agencies can

take measures to encourage competitive pharmaceutical sponsorship of

this drug—and thus new, independent, large-scale, unbiased clinical

trials—to explore fully its therapeutic dimensions in the treatment of

cancer and, possibly, AIDS. In so doing, these agencies will move to

rectify past ethical and scientific deficits and assume new high

ground in the sponsorship of measures beneficial to the public health

of peoples everywhere.

 

Recommendation . For those who may be a candidate for HS therapy, we

recommend you take a copy of this entire statement to your physician,

together with a copy of the published, controlled clinical trials

indicating efficacy and safety of HS, which can be found on our

website: scri.ngen.com. Your physician can then help determine a

choice of specific therapy for your condition and what role, if any,

HS may play in your particular therapy.

 

Joseph Gold, M.D., is director of the Syracuse Cancer Research

Institute and the developer of hydrazine sulfate as an anticancer drug.

 

ADDENDUM. It has come to the attention of the Syracuse Cancer Research

Institute that the National Cancer Institute has placed the following

misrepresentations on the Internet on June 18, 2004, repeated verbatim

on March 3, 2005

(http://www.nci.nih.gov/cancertopics/pdq/cam/hydrazinesulfate/healthprofessional\

/allpages/print),

in regard to hydrazine sulfate:

 

(1) " There is only limited evidence from animal studies that

hydrazine sulfate has anticancer activity. "

 

(2) " Hydrazine sulfate has shown no anticancer activity in

randomized clinical trials. "

 

The first sentence implies there have been no human studies that have

demonstrated the anticancer activity of hydrazine sulfate. But, as NCI

well knows, there have been many controlled human studies

demonstrating the anticancer activity of hydrazine sulfate, dating

from as far back as 1975 and published in leading peer-reviewed cancer

journals which circulate worldwide (cited in references 15, 17, 23,

27, 29, 34, 35, 41, 78).

 

The second sentence states categorically there have been no randomized

clinical trials demonstrating the anticancer activity of hydrazine

sulfate. RCTs represent the " gold standard " of clinical trials, in

that they are prospectively randomized, placebo-controlled,

double-blind and thus tend to minimize study bias from all sources.

But NCI knows there have been four such randomized clinical trials

demonstrating the anticancer activity of hydrazine sulfate (references

27, 34, 35, 41), all of which NCI has been aware from the very beginning.

 

NCI knows that the above statements it has currently placed on the

Internet are simply not true.

 

 

 

REFERENCES

 

1. Gold, J. Proposed treatment of cancer by inhibition of

gluconeogenesis. Oncology 22:185-207, 1968.

 

 

2. Gold, J. Inhibition of Walker 256 intramuscular carcinoma in

rats by administration of hydrazine sulfate. Oncology 25:66-7l, 1971.

 

 

3. Gold, J. Cancer cachexia and gluconeogenesis. Ann. N.Y. Acad.

Sci. 230:103-110, 1974.

 

 

4. Gold, J. Inhibition by hydrazine sulfate and various hydrazides

of in-vivo growth of Walker 256 intramuscular carcinoma, B-16

melanoma, Murphy-Sturm lymphosarcoma and L-1210 solid leukemia.

Oncology 27:69-80, 1976.

 

 

5. Dilman, V.H., Anisomov, V.N., Kolosov, A.I. and Bulovskaya, L.N.

On the relationship between the activity of acetylations, growth of

experimental tumors and efficacy of their suppression by hydrazine

sulfate. Oncology 33:219-221, 1976.

 

 

6. Grubbs, B., Rogers W. and Cameron, I. Total parenteral nutrition

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36:216-223, 1979.

 

 

7. Gold, J. Enhancement by hydrazine sulfate of antitumor

effectiveness of Cytoxan, Mitomycin C, Methotrexate and Bleomycin, in

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8. Tretyakov, A.V. and Filov, V.A. The mechanism of potentiation by

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9. Gold, J. Potentiation by Clofibrate of in-vivo tumor inhibition

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10. Gold, J. Hydrazine sulfate and cancer cachexia. Nutr. Cancer

1:4-9, 1979.

 

 

11. Gold, J. Inhibition of gluconeogenesis at the

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12. Gold, J. Inhibition of gluconeogenesis at the

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13. Hanley, J.M. Letter to the director of the National Cancer

Institute, March 8, 1976 .

 

 

14. Schonfeld, R.G. Letter to Congressman James M. Hanley, March 19,

1976.

 

 

15. Seits, J.F., Gershanovich, M.L., Filov, V.A., et al.

Experimental and clinical data on the antitumor action of hydrazine

sulfate. Vopr. Onkol. 21:45-52, 1975.

 

 

16. Schonfeld, R.G. Letter to Dr. Joseph Gold, director, Syracuse

Cancer Research Institute, Syracuse, New York.

 

 

17. Gershanovich, M.L., Danova, L.A. , Kondratyev, V.B., et al.

Clinical data on the antitumor activity of hydrazine sulfate. Cancer

Treat. Rep. 60:933-935, 1976.

 

 

18. Gold, J. Use of hydrazine sulfate in terminal and preterminal

cancer patients: results of Investigational New Drug (IND) study in 84

evaluable patients. Oncology 32:1-10, 1975.

 

 

19. Ochoa, M., Jr., Wittes, R.E. and Krakoff, I.H. Trial of

hydrazine sulfate (NSC-l500l4) in patients with cancer. Cancer

Chemother. Rep. 58:1151-1154, 1975.

 

 

20. American Cancer Society. Unproven methods of cancer management:

hydrazine sulfate. Ca—A Cancer Journal for Clinicians 26:108-110, 1976.

 

 

21. Gershanovich, M.L. and Filov, V.A. Hydrazine sulfate in late

stage cancer: completion of initial clinical trials in 225 evaluable

patients. Proc. Am. Assoc. Cancer Res. 20:240, 1979.

 

22. Horwitz, N. Top Ca groups polarized on Russian cachexia study.

Medical Tribune, May 16, 1979 .

 

 

23. Gershanovich, M.L., Danova, L.A. , Ivin, B.A. and Filov, V.A.

Results of clinical study of antitumor action of hydrazine sulfate.

Nutr. Cancer 3:7-12, 1981.

 

 

24. Spremulli, E., Wampler, G.L. and Regelson, W. Clinical study of

hydrazine sulfate in advanced cancer patients. Cancer Chemother.

Pharmacol. 3:121-124, 1979.

 

 

25. Gold, J. Incompatibility of hydrazine sulfate and pentobarbital

in the treatment of tumor bearing animals. Proc. Am. Assoc. Cancer

Res. 18:250, 1977.

 

 

26. Regelson, W. The `grand conspiracy' against the cancer cure. J.

Am. Med. Assoc. 243:337-339, 1980.

 

 

27. Chlebowski, R.T., Heber, D., Richardson , B. and Block, J.B.

Influence of hydrazine sulfate on abnormal carbohydrate metabolism in

patients with cancer cachexia. Cancer Res. 33:867-871, 1984.

 

 

28. DeVita, V.T., Jr., Hellman, S. and Rosenberg , S.A. (eds.).

Cancer, Principles & Practice of Oncology, 2 nd Ed., J. B. Lippincott

Co.: Philadelphia , 1985, pp. 2333-2344.

 

 

29. Filov, V.A., Ivin, V.A. and Gershanovich, M.L. (eds.). Medical

Therapy of Tumors, U.S.S.R. Ministry of Health: Leningrad , l983, pp.

92-139.

 

 

30. Chlebowski, R.T., Heber, D., Richardson , B. and Block, J.B.

Influence of hydrazine sulfate (HS) on carbohydrate metabolism in

cancer cachexia: a randomized, placebo-controlled trial. Proc. Am.

Soc. Clin. Oncol. 1:59, 1982.

 

 

31. Chlebowski, R.T., Heber, D., Richardson, B., et al. Association

between improved carbohydrate metabolism and weight maintenance in

hydrazine sulfate treated patients with cancer cachexia. Proc. Am.

Soc. Clin. Oncol. 2:95, 1983.

 

 

32. Chlebowski, R.T. Letter to Robert E. Wittes, M.D., Associate for Cancer Therapy Evaluation, National Cancer Institute,

April 19, 1985.

 

 

33. Personal communication, Nackey Scripps Loeb, publisher, The

Union Leader, Manchester , New Hampshire .

 

 

34. Chlebowski, R.T., Bulcavage, L., Grosvenor, M., et al. Hydrazine

sulfate in cancer patients with weight loss: a placebo-controlled

experience. Cancer 59:406-410, 1987.

 

 

35. Tayek, J.A., Heber, D. and Chlebowski, R.T. Effect of hydrazine

sulphate on whole-body protein breakdown measured by14 C-lysine

metabolism in lung cancer patients: Lancet 2:241-244, 1987.

 

 

36. Chlebowski, R.T., Bulcavage, L., Grosvenor, M., et al. Influence

of hydrazine sulfate on survival in non-small-cell lung cancer: a

randomized, placebo-controlled trial. Proc. Am. Soc. Clin. Oncol.

6:175, 1987.

 

 

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