Cellular accumulation of antineoplaston AS21 in human hepatoma cells.

Antineoplaston AS2-1 is a mixture of sodium salts of phenylacetic acid (PAA) and phenylacetylglutamine (PAG) in the ratio 4:1. The uptake of both compounds has been examined in human hepatoma cell line, Hep G-2. The accumulation of PAA was characterized by temperature sensitivity, saturability and energy dependency. Organic anions (probenecid, p-aminonohippuric acid and stilbene) inhibited PAA uptake suggesting the involvement of organic anion system in PAA transport. PAG cellular uptake exhibited dependency on metabolic energy, since the accumulation was sensitive to lowered temperature as well as to replacement of sodium ions by choline in the incubation medium. In contrast, the process showed tolerance to lithium ions as a substitute to sodium ions. This finding, together with the strong inhibition of PAG accumulation by histidine and glutamine, indicates that system N, known to be specific for hepatic tissue and the glutamine-preferring amino acid transport system, mediates PAG uptake. We conclude that PAG, through competition with glutamine for the same membrane carrier, may reduce glutamine transport leading to intracellular glutamine depletion. The physiological consequence of this biochemical event could be critical to cancer cells and therefore might contribute to the mechanism of antineoplaston AS2-1 action.

The influence of antineoplaston A5 on particular subtypes of central dopaminergic receptors.

A new therapeutic strategy for the treatment of Parkinson's disease (PD) is based on providing trophic support for degenerating dopaminergic (DA) neurons. It can be accomplished by administration of neurotrophic factors, or inducing astrocytes to differentiate and produce such factors. Antineoplaston A5 (A5), which is a naturally-occurring cytodifferentiating agent, may induce astrocytes to undergo normal differetiation, produce neurotrophic factors and alleviate the symptoms of PD. This paper describes studies on the influence of A5 on subtypes of central DA receptors by measuring the potency of haloperidol catalepsy in rats. A5, D1 agonist, and D1 D2 antagonists were given i.p. and D2 agonist s.c. for three consecutive days. Haloperidol catalepsy was measured by the method of Costall and Nylor. The degree of catalepsy was assessed every 30 min for 24 h and statistically evaluated using the Student's t-test. The results confirmed that A5 significantly attenuated catalepsy and stimulates dopamine D2 receptors. It reverses catalepsy induced by haloperidol and D2 antagonists, but increases cataleptogenic activity if given in combination with the D2 agonist. This leads to the conclusion that A5 as a naturally-occurring agent neutralizes both hyper- and hypoactivity of central dopaminergic structures. Besides possible use as an antiparkinsonism agent, A5 may find application in the treatment of other disturbances of dopaminergic transmission.

The influence of antineoplaston A5 on the central dopaminergic structures.

Antineoplastons are naturally occurring cytodifferentiating agents. Chemically, antineoplastons are medium and small sized peptides, amino acid derivatives and organic acids which exist in blood, tissues and urine. In clinical trials in advanced cancer, in addition to the anticancer activity it was observed that patients suffering from both cancer and Parkinson's disease exhibited marked improvement in parkinsonian symtomatology when treated with antineoplaston A5. The present study was designed to analyse the influence of A5 on central dopaminergic structures. Mice and rats were given A5 intraperitoneally at three different dosage levels. Experiments conducted included spontaneous locomotor activity, amphetamine-induced yawning and erections, catalepsy, the effect on the level and utilization of noradrenaline and dopamine in the brain and the influence of prolonged and chronic treatment on the haloperidol-induced catalepsy. It has been demonstrated that A5 stimulates the central dopaminergic receptors. It diminishes the cataleptic response to haloperidol and enhances the incidence of apomorphine-induced yawning. Biochemical studies demonstrated increased concentration of dopamine and noradrenaline in the brain and diminished utilization of both catecholamines.

Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1.

Successful treatment of advanced cancer of the prostate which no longer responds to hormonal manipulation continues to be a difficult task. The present study describes the results of treatment of the first fourteen patients in Phase II clinical trials with Antineoplaston AS2-1 (AS) and low-dose diethylstilbestrol (DES). The study involved thirteen patients diagnosed with stage IV and one patient with stage II adenocarcinoma of the prostate. The ages of the patients were between 54 and 88. The previous therapy included prostatectomy, orchiectomy, radiation therapy and treatment with DES, LHRH agonist (LH), flutamide (FL), aminoglutethimide and immunotherapy. After initial response to such treatments, the disease continued to progress. The majority of patients showed progression of the disease after treatment with LH and FL. The current treatment program consisted of administration of AS and DES. The treatment was given orally daily. The majority of patients received from 97 to 130 mg/kg/24 h of AS and from 0.01 to 0.02 mg/kg/24 h of DES. The treatment was administered from 64 to 425 days and was free from significant side effects due to AS. The dose of DES was lower than usual, and only some patients experienced mild side effects typical for DES. Only two patients showed progression of the disease. Complete remission was obtained in two patients and partial remission in three patients. Stabilization of the disease with objective improvement was determined in seven patients. The first patient enrolled in the program has been in complete remission for 17 months and off the treatment for 16 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial clinical study with antineoplaston A2 injections in cancer patients with five years' follow-up.

This paper describes Phase I clinical studies of Antineoplaston A2 injections. The studies involved 15 patients diagnosed with advanced neoplastic diseases including cancers of the breast, bladder, lung, kidney, oesophagus, colon and liver, mesothelioma and glioma. Antineoplaston A2 was administered in divided doses daily intravenously through a subclavian vein catheter. The treatment was given from 53 to 358 days. The highest dosage administered was 147 mg/kg/24 h. Only minimal adverse effects were noticed sometime during the treatment, including fever, chills and myalgia. Desirable side-effects included increase of platelet and white blood cell counts, hypertrophy of epidermis and decrease of cholesterol and triglyceride levels. Nine patients showed objective response to the treatment. Cases of complete remission included adenocarcinoma of the lung, mesothelioma, metastatic liver and bladder cancers. In an additional case of breast cancer, the patient obtained complete remission of liver metastasis and stabilization of bone metastases. Partial remission was accomplished in cancers of the breast and oesophagus. Three patients, including cases of adenocarcinoma of the lung, mesothelioma and bladder cancer, were in complete remission for over five years.

In vitro cancer growth inhibition and animal toxicity studies of antineoplaston A3.

Antineoplaston A3 is an oxidized mixture of small and medium size peptides and amino acid derivatives isolated from human urine. The purpose of this study was to evaluate the growth inhibitory effect of Antineoplaston A3 on cancer cells in vitro and its toxicity in mice. The growth inhibitory studies were carried out on breast carcinoma cells HBL-100. The cells were plated at 1000 cells per flask in L-15 medium and supplemented with 10% foetal bovine serum and antibiotics. Two different experiments were performed: to study dose response; and to investigate duration exposure. To establish dose response, Antineoplaston A3 was added to each flask to a final concentration of 0.05, 0.1, 0.2 and 0.4 mg/ml. Two flasks in each test were added with the same amount of medium to serve as control. The flasks were incubated at 37 degrees C for 6 days, then fixed and stained, after which colonies were counted. Results were expressed as percentage of control. In duration exposure experiments Antineoplaston A3 was added to the final concentration of 0.4 mg/ml. After 24, 48 and 72 h of exposure to Antineoplaston A3, the flasks were returned to normal growth medium and colonies were again counted. Dose response to Antineoplaston A3 was as follows (average of 3 replications +/- standard error): 0.05 mg/ml, 100% +/- 0; 0.1 mg/ml, 79.0% +/- 14.4; 0.2 mg/ml, 4.3% +/- 6.6; 0.4 mg/ml, 0% +/- 0.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I clinical studies of antineoplaston A3 injections.

Antineoplaston A3 is an oxidated mixture of small peptides and amino acid derivatives isolated from human urine which have shown antineoplastic activity in tissue culture and low toxicity in mice. Twenty-four patients diagnosed with 25 cases of neoplastic diseases were involved in the studies. The patients' diagnoses included: adenocarcinoma of the prostate, stage IV (7 cases); adenocarcinoma of the breast, stage IV (3); adenocarcinoma of the colon and rectum, stage IV (3); adenocarcinoma of the colon, status post resection (1); adenocarcinoma of the lung, stage III (2); squamous cell carcinoma of the lung, stage III (2); adenocarcinoma of the pancreas, stages II and IV (2); and single cases of adenocarcinoma of the kidney, stage IV; malignant fibrohistiocytoma, stage IV; glioblastoma multiforme, stage IV; basal cell epithelioma; and transitional cell carcinoma of the bladder, grade II. Only patients who had over six weeks' anticipated survival and who continued the treatment for over six weeks were eligible. In 23 patients, Antineoplaston A3 was administered in divided doses daily i.v. through a subclavian vein catheter. In one patient, the injections were given i.m. The length of treatment was from 44 to 478 days and the highest dosage was 76 mg/kg/24 h. Side-effects associated with treatment included febrile reaction (4 patients), vertigo (2), headache (2), flushing of the face, nausea and tachycardia (1 each). Adverse reactions were mild and occurred only once during the entire course of treatment. Desirable side-effects included increase of platelet count, increase of white blood cell count and increase of reticulocyte count. At the end of the study, there were 5 cases of complete remission, 5 of partial remission, nine of stable disease and six of increasing disease. The patients who obtained complete remission were diagnosed with cancers of the bladder, prostate, colon, and basal cell epithelioma. In view of its very limited toxicity and the interesting responses obtained, Antineoplaston A3 was submitted for Phase II clinical trials to establish its usefulness in cancer treatment.

Tissue culture and animal toxicity studies of antineoplaston A5.

Antineoplaston A5 is a mixture of small to medium size peptides and amino acid derivatives isolated from human urine. This report describes growth inhibition by Antineoplaston A5 of human cell carcinoma line HBL-100 and human leukaemic cell line Jurkat, and acute and chronic toxicity studies in mice. The inhibitory effect of Antineoplaston A5 on HBL-100 cells was tested at concentrations varying from 0.125 mg/ml to 0.5 mg/ml and at exposure durations varying from 24 to 96 h. The tests on Jurkat cells were carried out at concentrations varying from 0.1 mg/ml to 0.8 mg/ml and exposure durations varying from 24 to 120 h. The results from HBL-100 cells, shown as percentage of survival, were as follows: at 0.125 mg/ml 58%; at 0.25 mg/ml 14%; at 0.5 mg/ml 0. Exposure of HBL-100 cells to 0.5 mg/ml of Antineoplaston A5 for 24, 48, 72 and 96 h reduced survival to 55%, 10%, 4% and 0 of the control respectively. The results for suspension culture of Jurkat were as follows: The control cells showed a 7.7-fold increase in cell number during the incubation period, while the cells treated with 0.8 mg/ml of Antineoplaston A5 showed a steady decrease in cell number. At the end of 120 hours' incubation, only 1% of the cells was still viable. The growth inhibition patterns for dosages ranging from 0.4 mg/ml to 0.1 mg/ml were unique; instead of decreasing, the cell numbers in these flasks kept increasing, although at a slower pace during the initial 72 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I clinical studies of antineoplaston A5 injections.

Antineoplaston A5 is a mixture of small peptides and amino acid derivatives isolated from human urine which show a unique pattern of growth inhibition in the tissue culture of human neoplastic cells and no significant animal toxicity. Clinical trials described in this paper involved 15 patients diagnosed with advanced neoplastic diseases. The patients' diagnoses included: lung cancer, stage III (4 cases); breast, stages III and IV (3); colorectal, stage IV (2); bladder (2); and single cases of adenocarcinoma of the jejunum, stage IV; adenocarcinoma of the prostate, stage IV; adenocarcinoma of the ovary, stage IV and astrocytoma, grade IV. Antineoplaston A5 was administered daily in divided doses intravenously through a subclavian vein catheter. The formulation was given from 47 to 130 days. The highest dosage attained was 153 mg/kg/24 h. Adverse effects included febrile reaction in five patients, arthralgia in one patient and premature beats and pressure in the chest in one patient. The side-effects were very mild and usually experienced only once during the entire course of treatment. Desirable side-effects included increase of platelet count, increase of white blood cell count and hypertrophy of epidermis. Nine patients (60%) had objective response to the treatment. They were diagnosed with cancer of the lung (3 patients), breast (2), colorectal (2) and bladder (2). Four patients had increasing disease and two patients were classified as having stable disease without objective improvement.