pyrazofurin and Neoplasms

Recent advances in the rational design of anticancer chemotherapy in this laboratory have been based on strategic differences between normal and cancer cells. On the basis of our identification of quantitative biochemical markers and characteristic enzymic and metabolic programs of neoplastic cells, we have designed single and combination drug treatments. This chemotherapeutic approach aims at specific enzymic targets in cancer cells that are closely linked with transformation and progression. With the identification of markedly increased concentrations of CTP, dATP, dGTP, dCTP and dTTP in neoplasms, there should be an operational advantage in directing chemotherapy to depress the concentration of these metabolites elevated in cancer cells, because a drug-imposed curtailment of these metabolites might destroy cancer cells that depend more stringently on the increased concentrations of these nucleotides. Experiments in tissue culture and in solid tumors utilizing treatment schedules with pyrazofurin in combination with galactosamine, and the use of adriamycin, succeeded in achieving profound alterations in the nucleotide concentrations of cancer cells.

Topics: Amides; Animals; Antineoplastic Agents; Deoxyribonucleotides; Doxorubicin; Drug Therapy; Humans; Liver Neoplasms, Experimental; Mice; Neoplasms; Neoplasms, Experimental; Pyrazoles; Rats; Ribonucleosides; Ribonucleotides; Ribose; Thymidine Kinase

Topics: Adolescent; Adult; Aged; Amides; Animals; Carcinoma 256, Walker; Cell Division; Cell Line; Female; Humans; In Vitro Techniques; Leukemia, Experimental; Leukemia, Myeloid, Acute; Male; Mice; Middle Aged; Mouth Mucosa; Neoplasms; Orotic Acid; Pyrazoles; Pyrimidine Nucleotides; Ribonucleosides; Ribose; Uridine

Sixty-one patients with advanced disseminated cancer were given progressively increasing doses of pyrazofurin to evaluate toxicity patterns and to establish the dosage that produces maximum therapeutic effect with clinically tolerable toxicity. The drug was given by intravenous injection over 5-day courses repeated every 2--3 weeks. Toxic reactions included stomatitis, myelosuppression, skin rash, erythema, proctitis, and occasional nausea and vomiting. Stomatitis was the dose-limiting toxicity and it occurred in 32 patients. Myelosuppression was mild to moderate. Of 75 evaluable courses for marrow toxicity, leukopenia occurred in 14 and thrombocytopenia in 28. Thrombocytopenia was apparently dose-independet. Marrow recovery was complete by day 21 of therapy. Twelve patients developed mild or severe cutaneous toxicity depending on dose. When mild, the skin changes consisted of self-limited erythema or rash, and when severe, bullous lesions and skin ulcers were also observed. Proctitis occurred in six patients and was associated with severe stomatitis. Nausea and vomiting were occasional and mild. There was no evidence of liver or renal toxicity. All toxic manifestations other than marrow toxicity were dose-related. No responses were observed. A reasonable dose schedule is 45 mg/m2/day X 5 repeated every 3 weeks. We recommend that Phase II studies be pursued particularly in diseases that have been shown to be sensitive to the drug.

Topics: Aged; Amides; Antibiotics, Antineoplastic; Bone Marrow; Drug Administration Schedule; Drug Evaluation; Female; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Pyrazoles; Ribonucleosides; Ribose; Skin; Stomatitis

Topics: Amides; Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Half-Life; Humans; Infusions, Parenteral; Injections, Intravenous; Leukemia, Lymphoid; Leukocytes; Male; Neoplasms; Orotic Acid; Pyrazoles; Ribonucleosides; Ribose; Uric Acid