RESUMO
A novel schedule of 5-fluorouracil administration has been developed for biochemical modulation studies. In combination with the pyrimidine synthesis inhibitor PALA, 5-fluorouracil has been given as a 24-hour infusion, repeated weekly: a dose of 2600 mg/m2 is well tolerated. To identify a suitable dose of 5-fluorouracil as a single agent on this schedule, we treated 26 patients at doses ranging from 2800 to 3400 mg/m2 per week. Two-thirds of the patients had failed previous therapy, and most were symptomatic from their disease. Over half of the patients had metastatic colorectal cancer. The dose-limiting toxicity was diarrhea: Grade 3 or 4 toxicity occurred at every level tested. Twenty-two of the 26 patients required therapy interruption because of toxicity. The severity of this toxicity indicated that escalation of 5-fluorouracil on this schedule beyond the 2600 mg/m2 known to be tolerated in the PALA-containing regimen, would be impractical. Two patients, both with previously untreated colorectal cancer, had partial remissions lasting three and five months respectively. This dose-intense schedule of 5-fluorouracil administration will be explored further in large-scale randomized trials.
Assuntos
Fluoruracila/administração & dosagem , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Esquema de Medicação , Gastroenteropatias/induzido quimicamente , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neutropenia/induzido quimicamente , Projetos PilotoAssuntos
Antineoplásicos/farmacologia , Glutationa/fisiologia , Antimetabólitos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Butionina Sulfoximina , Reparo do DNA/efeitos dos fármacos , Resistência a Medicamentos , Feminino , Glutationa/metabolismo , Humanos , Melfalan/administração & dosagem , Metionina Sulfoximina/administração & dosagem , Metionina Sulfoximina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismoRESUMO
Phosphonacetyl-L-aspartate (PALA) is a rationally-synthesized analog of the transition-state intermediate in the formation of carbamyl aspartate from carbamyl phosphate and aspartic acid by aspartate carbamyl transferase (ACTase). PALA is thus a potent inhibitor of the enzyme (Ki about 10(-8) M for ACTases of various origins), which in whole cells blocks the de novo synthesis of pyrimidines. In vivo, low doses of PALA inhibit whole body pyrimidine synthesis. While this action is cytotoxic in vitro, extensive human testing demonstrates that PALA alone is devoid of selective antitumor activity. Recent interest in the therapeutic action of PALA derives from the demonstration that its action potentiates the cytotoxicity of several cytotoxic drugs, notably 5-fluorouracil (5-FU). Results from clinical trials of PALA and 5-FU in combination in colorectal cancer suggest that biochemical modulation with regimens which follow the principles determined in preclinical studies may enhance the efficacy of current therapy.