iv.vitamin C vs. cancer

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Intravenous Ascorbate as a Chemotherapeutic and Biologic Response

Modifying Agent

by The Center for the Improvement of Human Functioning,

International, Inc., Bio-Communications Research Institute

 

(Emphasis added by DoctorYourself.com editor Andrew Saul)

 

More papers posted in their entirety at

http://www.brightspot.org/Vitcresearch.htm

 

Introduction

For over 15 years we have studied high dose intravenous ascorbic acid

(IAA) as an adjunctive therapy for cancer patients. Initially, doses

of 15 g per infusion were used, once or twice per week. These doses

improved patient's sense of well being, reduced pain, and in many

cases prolonged life beyond prognostications of oncologists.

 

Twelve years ago, we used infusions of 30 grams of intravenous

ascorbic acid, twice per week, and found that metastatic lesions in

the lung and liver of a man with a primary renal cell carcinoma

disappeared in a matter of weeks (1). At that time we believed IAA

was useful for patients with cancer solely through two biological

response modifier mechanisms: increased production of extracellular

collagen ( " walling off' the tumor as proposed by Cameron and Pauling)

and enhancement of immune function. We subsequently reported a case

of resolution of bone metastases in a patient with primary breast

cancer (1A) using infusions of 100 grams, once or twice per week (2).

 

In a recent publication (3) we presented evidence that ascorbic acid

and its salts (AA) could be more than biological response modifiers.

We found that ascorbic acid is preferentially toxic to tumor cells

suggesting that it could be useful as a chemotherapeutic agent.

Preferential toxicity occurred in vitro in multiple tumor cell types.

We also presented data suggesting that plasma concentrations of

ascorbate required for killing tumor cells were achievable in humans.

Others have described in vivo toxicity in multiple tumor types and

animal models (4-8).

 

Here we wish to summarize our experience using IAA for approximately

50 patients with cancer. We include our protocol, precautions, and

case studies of two patients treated for metastatic renal cell

carcinoma.

 

Treatment rationale

From our studies (3) we concluded that:

 

Tumor cells are more susceptible to the effects of high-dose,

ascorbate-induced peroxidation products because of a relative

catalase deficiency; and,

 

Concentrations of ascorbate high enough to kill tumor cells likely

can be achieved in humans.

 

Subsequently we tested samples of human serum from patients receiving

IAA, and confirmed that AA concentrations can reach levels that are

cytotoxic to tumor cells in vitro. Using densely populated

monolayers, three-dimensional hollow-fiber tumor models, and human

serum as a growth medium to closely mimic what occurs in vivo, we

found that an AA concentration of 400 mg/dL effectively kills most

tumor cell types. Originally we reported that a concentration of 40

mg/dL was adequate (3). Those early data were generated from in vitro

studies using sparsely populated cell monolayers and standard tissue

culture medium

 

(Figure 1 (which may be seen in the original paper posted at

http://www.brightspot.org/intravenousascorbatearticle2.htm )shows the

responses to increasing doses of ascorbate of four human tumor cell

lines grown in dense monolayers in a medium of human serum.)

 

Figure 1 Caption:

Response to sodium ascorbate (mean of 12 samples) of tumor cell lines

Mia PaCa-2 (human pancreatic carcinoma). SK-MEL-28 (human melanoma),

SW-620 (human colon carcinoma), and U-2-OS (human osteogenic

sarcoma), all from ATCC, Rockville, MD. Results reflect total viable

cells. Maintenance medium was DMEM High-glucose culture medium

(Irvine Sci.) wf 10% heat-inactivated fetal calf serum + antibiotics

+ Fungizone, 5% CO2 humidified incubator at 37 degrees C.

Experimental medium was human serum from patients with diagnoses of

respective human tumors. Cultured for 3 days after supplementation of

ascorbate. Seeded with 24,000 celIs Avell in 96-well culture plates

(Nune). Absolute quantitation of live cells determined using

previously described microplate fluorometer method (16).

 

Figure 2 Caption:

Plasma ascorbate concentrations during infusion of 65 grams ascorbic

acid in 500 ml sterile water at a rate of one gram AA per minute.

Whole blood was taken via a heparin lock from the antecubital vein of

the arm contraleral to the arm receiving the IV infusion. Plasma AA

concentrations were determined using high performance liquid

chromatograpy. Patient I was a 74-year-old male who had a diagnosis

of non-metastatic prostate carcinoma, who had received more than 30

IAA infusions in the two years prior to the study. Patient 2 was a 50-

year-old male with a diagnosis of non-Hodgkin's lymphoma who had

received l6 IAA infusions prior to study. Patient 3 was a 69 year old

male with a diagnosis of metastatic carcinoma of the jejunum who had

received 16 IAA infusions prior to study.

 

Figure 2 depicts plasma ascorbate levels of three representative

patients given 65 grams of ascorbate over 65 minutes. Patient 1 with

localized prostate cancer was clinically well and had received IAA in

the past; he achieved a peak plasma concentration of 702 mg/dL.

Patients 2 and 3, had diagnoses of non-Hodgkin's lymphoma, and

metastatic carcinoma of the jejunum, respectively. Both had received

several IAA infusions at the time of study, yet achieved lower plasma

AA concentrations of 309 mg/dL (patient 3), and 396 mg/dL (patient

2).

 

From the data in both Figures 1 and 2, one can see that the

concentrations required to kill tumor cells can be achieved at least

briefly in human plasma. Figure 2 suggests the need to measure post-

IAA plasma ascorbate concentrations to determine if patients are

achieving what we expect are adequate concentrations.

 

Infusion Protocol

 

Treatment choice

Treatment of cancer with IAA should never be considered to replace an

effective, proven treatment. It should only be considered in:

 

Cases of treatment failure using proven methods cases with no known

effective treatments; and,

 

Cases in which it is used as an adjunct to proven treatments.

 

Because IAA treatment is experimental an appropriate informed consent

form should be read, understood, and signed by the patient.

 

Precautions and side effects

The side effects of IAA in our experience are rare. However, there

are contraindications and potential side effects to be considered.

 

1. Although it has been reported only once in the literature, tumor

necrosis, hemorrhage, and subsequent death after a single intravenous

10 gram dose of AA, as reported by Campbell and Jack (10), should be

the highest priority concern for the safety of IAA for cancer

patients. For this reason, we always begin with a small dose (see

Infusion).

 

2. Another report described acute oxalate nephropathy in a patient

with bilateral ureteric obstruction and renal insufficiency who

received 60 gram IAA (11). We have also heard one case report of a

patient with colon carcinoma, receiving daily IAA, who developed

nausea and vomiting and was hospitalized for dehydration (12). Both

cases show the need to ensure that patients have adequate renal

function, hydration, and urinary voiding capacity. To these ends, our

baseline lab tests include a serum chemistry profile and urinalysis.

 

3. Hemolysis can occur in patients with a red cell glucose-6-

phosphate dehydrogenase (G6PD) deficiency. We therefore test G6PD on

all patients before beginning IAA infusions.

 

4. Localized pain at the infusion site can occur if the infusion rate

is too high. This is usually corrected by slowing the rate.

 

5. Because ascorbate is a chelating agent, some individuals may

experience shaking due to low serum calcium. This is treated by a

slow (1 cc per minute) intravenous push of 10 cc's of calcium

gluconate.

 

6. Rivers (13) reported that high dose IAA is contraindicated in

renal insufficiency, chronic hemodialysis patients, unusual forms of

iron overload, and oxalate stone formers. However, oxalate stone

formation may be considered a relative contraindication. Two groups

of researchers (14,15) demonstrated that magnesium oxide (300 rng/d

orally) and vitamin B6 (10 mg/d orally) inhibited oxalate stone

formation in stone formers.

 

7. Given the amount of fluid which is used as a vehicle for the

ascorbate and the sodium hydroxide/sodium bicarbonate used to adjust

the pH, any condition which could be adversely affected by increased

fluid or sodium is relatively contraindicated. For example:

congestive heart failure, ascites, edema, etc.

 

8. As with any intravenous site, infiltration is always possible.

 

9. Ascorbate should only be given by intravenous drip. It should

never be given IV push, as the osmolality of high doses are capable

of sclerosing peripheral veins, nor should it be given

intramuscularly or subcutaneously. There is always a trade-off

between fluid volume and osmolality. We have found an osmolality of

less than 1200 milliOsmal to be tolerated well by most patients

(Table 1, which may be seen in the original paper).

 

Baseline work-up

Prior to administering large quantities of ascorbate, we gather the

following information for a baseline and as a way to monitor

therapy:

 

Serum chemistry profile with electrolytes

Complete blood count with differential

Red blood cell G6PD

Urinalysis

Patient weight

Tumor type/staging

Appropriate serum tumor markers

Appropriate CT, MRL, bone scans, and x-ray imaging

 

Table 1 Caption:

Osmolality of various amounts of sodium ascorbate/ascorbic acid in

sterile water and Ringer's Lactate (mOsm; isotonic = 300 mOsm).

Hypotonic mixtures are underlined: useful mixtures from isotonic to

1200 mOsm are in bold. An equal volume of IV solution is removed from

the bag or bottle, prior to adding concentrated sodium

ascorbate/ascorbic acid solution (500 mg/mL).

 

Infusion solution

In high-dose ascorbate therapy, many intravenous solutions are

hypertonic. This does not seem to present a problem as long as the

infusion rate is low enough and the tonicity does not exceed 1200

milliOsmal (mOsm). We generally infuse AA mixed with Ringer's lactate

(RL) solution for AA amounts up to 15 gram, and in sterile water for

larger amounts of AA. We presently use a sodium ascorbate/ascorbic

acid mixture Containing 0.91 moles of sodium per mole of ascorbate

(500 mg AA/mL, pH range 5.5-7.0, Merit Pharmaceuticals, Los Angeles,

California, and Maclaskey Pharmaceuticals, Wichita, Kansas). Table I

shows the osmolalities of commonly prepared solutions.

 

Infusion

As indicated in the precautions, a small starting dose of 15 gram AA

in 250 mL RL over 1 hr is recommended. The patient is watched closely

for any adverse effects. The dose can then be gradually increased

over time. The infusion rate should not exceed 1 gram AA per minute;

0.5 gram/mm is well tolerated by most patients. Although there is

variability due to scheduling and tolerance, a typical protocol will

consist of the following infusions:

 

Week 1: 1 x 15 g infusion per day, 2-3 per week

Week 2: 1 x 30 g infusion per day, 2-3 per week

Week 3: 1 x 65 g infusion per day, 2-3 per week

 

The dose is then adjusted to achieve transient plasma concentrations

of 400 mg/dL, 2-3 infusions per week.

 

According to our working hypothesis, the goal of the infusions is to

raise plasma ascorbate concentration above the tumor-cytotoxic level

for as long as possible. Because the ascorbate is so readily cleared

by the kidney, the optimal infusion rate will result in tumor-

cytotoxic plasma levels of ascorbate for the longest time periods--

and hopefully, maximum tumor cell killing.

 

We advise patients to orally supplement with 4 grams ascorbate daily,

especially on the days when no infusions are made, to help prevent a

possible scorbutic " rebound effect. "

 

Case histories

We have seen patients with almost every type of solid tumor in our

clinic. Many of them have received IAA, with various degrees of

success. Our cases include a patient with cancer of the head of the

pancreas who lived for 3.5 years with IAA as sole therapy, resolution

of bone metastases in patients with breast cancer, many patients with

non-Hodgkin's lymphoma (none of whom have died from their disease),

resolution of primary liver carcinoma tumors, resolution of and

reduction in size of metastatic colon carcinoma lesions, and

resolution of metastatic lesions and over 3-year survival in patients

with widely metastatic ovarian carcinoma. We plan to present a full

compilation of cases in another communication.

 

We have seen only two cases of metastatic renal cell carcinoma,

considered a uniformly untreatable disease. Because the results were

so dramatic, people with this disease could potentially benefit the

most from IAA treatment.

 

Following are those two cases.

 

Case 1

A 52-year-old white female with a history of renal cell carcinoma was

seen in our clinic for the first time in October, 1996.In September

1995, shortly after diagnosis of a primary tumor in her left kidney,

a nephrectomy was performed. Histology confirmed renal cell

carcinoma. No evidence of metastases was found at that time. In March

1996, metastases to the lungs were found on chest x-ray film. In

September 1996, a chest x-ray film revealed 4 1- to 3-cm masses in

her lungs. One month later there were 8 1- to 3-cm masses in her

lungs (7 in right lung, 1 in left).No new medical, radiation, or

surgical therapies were performed prior to her visit to our clinic in

October 1996, when she began IAA therapy. Her initial dose was 15 g,

which increased to 65 g after 2 weeks, two per week. She was also

started on: N-acetyl cysteine (Vitamin Research Products, Carson

City, NV), 500 mg 1 p.o., QD; beta-1,3- glucan (a macrophage

stimulator, NSC-24, Nutrition Supply Corp., Carson City, NV), 2.5 mg

3 p.o. QD; fish oil (Super-EPA, Bronson Pharmaceuticals, St. Louis,

MO; 300 mg eicosatetraenoic acid, 200 mg docosahexaenoic acid), 1

p.o. TID; vitamin C, 9 g p.o. QD; beta-carotene (Beta Carotene 25,

Miller Pharmacal Group, Inc., Carol Stream, IL), 25,000 lU. 1 p.o.

BID; L-threonine (The Solgar Vitamin Co, Inc., Lynbrook, NY), 500 mg

p.o. QD (for a deficiency revealed by laboratory testing of serum);

Bacillus laterosporus (Lateroflora, International Bio-Tech U.S.A.,

San Marcos, CA), 280 mg, 2 p.o. QD for intestinal Candida a/b icans,

inositol hexaniacinate complex (Niaplex, Karuna Corp., Novato, CA;

500 mg niacin, 100 mcg chromium) 2 p.o. QD, and a no-refined-sugar

diet.

 

She continued IAA treatments until June 1997 when another chest x-ray

film revealed resolution of 7 of the 8 masses, and reduction in the

size of the 8th. According to the medical imaging report, " The

nodular infiltrates seen previously in the right lung and overlying

the heart are no longer evident and the nodular infiltrate seen in

left upper lung field has shown marked Interval decrease in size and

only vague suggestion of an approximately I cm density. "

 

The patient discontinued IAA treatments in June 1997. She has

continued on an oral nutritional support program since that time, and

at this writing (December 1997) is well with no evidence of

progression.

 

Case 2

In December 1985, a mass occupying the lower pole of the right kidney

was discovered in a 70- year-old white male. Pathology of the mass

after a radical nephrectomy confirmed renal cell carcinoma. He was

followed by an oncologist at another clinic. Approximately three

months after surgery, the patient's x-ray film and CT scan

showed " multiple pulmonary lesions and lesions in several areas of

his liver which were abnormal and periaortic lymphadenopathy. "

 

In March 1986 the patient was seen in our clinic (1). He decided not

to undergo

chemotherapy. Vie requested and was started on IAA, 30 g twice per

week. In April 1986, six weeks after the x-ray film and CT scan

studies, the oncologist's report stated,

 

" . . . the patient returns feeling well. His exam is totally normal.

His chest x-ray shows a dramatic improvement in pulmonary nodules

compared to six weeks ago. The periaortic lymphadenopathy is

completely resolved..., either he has had a viral infection with

pulmonary lesions with lymphadenopathy that has resolved or (2) he

really did have recurrent kidney cancer which is responding to your

vitamin C therapy. "

 

The oncology report in July 1996 stated, " there is no evidence of

progressive cancer. He looks well . . . chest x-ray today is totally

normal. The pulmonary nodules are completely gone. There is no

evidence of lung metastasis, liver metastasis or lymph node

metastasis today, whatsoever. "

 

In 1986 the patient received 30 g infusions twice-weekly for 7

months. The treatments were then reduced to once per week for 8 more

months. For an additional 6 months he received weekly, 15 g IAA

infusions. During and after treatments, the patient reported no

toxicities, and his blood chemistry profiles and urine studies were

normal. The patient continued well, and was seen periodically at our

clinic until early 1997 when he died, cancer-free, at age 82, 12

years after diagnosis.

 

Conclusion

We believe that IAA has potential as a chemotherapeutic agent. We

hope our protocols for mixing and infusion of IAA, precautions to be

taken before and during its use, and clinical case reports will

justify further clinical trials and research with IAA for patients

with metastatic disease. We do not believe it is a cure for all

cancers. Although it shows promise as a sole therapy, particularly in

renal cell carcinoma, it should be used primarily as an adjunct to

other effective therapies.

 

Support

Our research is funded solely through donations from individuals. We

have neither sought nor received funding from government agencies. We

encourage readers to support our research. All donations to our 501

© 3 organization are tax-deductible.

 

Neil H. Riordan, PA-C

Hugh D. Riordan, M.D.

Ronald E. Hunninghake, M.D.

 

The Center for the Improvement of Human Functioning, International,

Inc.

3100 N. Hillside Ave., Wichita, Kansas 67219

 

Acknowledgments:

We would like to thank the Bio-Communications Research Institute

scientific staff who contributed to this research: Neil Riordan, P.A.-

C., Xiaolong Meng, MB.; Paul Taylor, B.S.; Jei Zhong, MB.; Kevin

Alliston, MS.; and Joseph Casciari, Ph.D. We thank Don R. Davis,

Ph.D., for editing this manuscript.

 

References

1. Riordan HD, Jackson JA, 'Schultz M. Case study: high-dose

intravenous vitamin C in the treatment of a patient with

adenocarcinoma of the kidney. J Ortho Med 1990; 5: 5-7.

 

2. Riordan N, Jackson JA, Riordan HD. Intravenous vitamin C in a

terminal cancer patient. J Ortho Med 1996; 11: 80-82.

 

3. Riordan NH, Riordan HD, Meng X, Li Y, Jackson JA. Intravenous

ascorbate as a tumor cytotoxic chemotherapeutic agent. Med Hypotheses

1 995; 44: 207-2 13.

 

4. Cohen MH, Krasnow SH. Cure of advanced Lewis lung carcinoma (LL):

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5. Lupulesco A. Vitamin C inhibits DNA, RNA and protein synthesis in

epithelial neoplastic cells. mdl Vit Nutr Res 1991; 61: 125-129.

 

6. Varga JM, Airoldi, L. Inhibition of transplantable melanoma tumor

development in mice by prophylactic administration of Ca-ascorbate.

Life Sciences 1983 ; 32: 1559-1564.

 

7. Pierson HE, Meadows GG. Sodium ascorbate enhancement of carbidopa-

levodopa methyl ester antitumor activity against pigmented B-16

melanoma. Cancer Res 1983; 43: 2047-205 I.

 

8. Chakrabarti RN, Dasgupta PS. Effects of ascorbic acid on survival

and cell-mediated immunity in tumor bearing mice. IRCS Med Sci 1984;

12: 1147-1 148.

 

9. Tsao CS, Dunham WB, Ping, YL. In vivo antineoplastic activity of

ascorbic acid for human mammary tumor. In vivo 1988; 2: 147-150.

 

10. Campbell A, Jack T. Acute reactions to mega ascorbic acid therapy

in malignant disease. Scot Med J 1979; 24: 151.

 

11. Wong K, Thomson C, Bailey RR, McDiarmid S, Gardner J. Acute

oxalate

nephropathy after a massive intravenous dose of vitamin C. Aust NZ J

Med 1994: 24.

 

12. Hanson, J. Personal communication, December 1, 1997.

 

13. Rivers JM. Safety of high-level vitamin C ingestion. In: Third

Conference on AA. Ann NY Acad Sci 1987; 498: 95-102.

 

14. Rattan V, Sidhu H, Vaidyanathan 5, Thind SK, Nath R. Effect of

combined

supplementation of magnesium oxide and pyridoxine in calcium-oxalate

stone formers. (Irol Res 1994; 22: 161-5.

 

15. Prien EL, Gershoff S F. Magnesium oxide-pyridoxine therapy for

recurrent calcium oxalate calculi. J Urol 1974; l 12: 509-512.

 

16. Riordan HD, Riordan NH, Meng X, Zhong Z, and Jackson JA. Improved

microplate fluorometer counting of viable tumor and normal cells.

Anticancer Res 1994: 927-932.

 

 

Reprinted with the kind permission of Dr. Hugh D. Riordan and the Bio-

Communications Research Institute.

 

 

 

 

Dr. Andrew Saul

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