ARA-C analogs.

Abstract

Ara-C, a phase-specific antitumor agent, is rapidly deactivated by the enzyme cytidine deaminase. A prolongation of the biological activity of ara-C can be achieved either by the concomitant use of a cytidine deaminase inhibitor or by the development of ara-C derivatives with increased resistance to deamination and a longer half-life in serum. Among such derivatives are cyclocytidine (cyclo-C), anhydro-ara-5-fluorocytidine (AAFC) and the N4-acyl-derivatives. AAFC has been recently shown to be active in human leukemias and in solid tumors of the digestive tract. The tolerance to AAFC is sufficient for clinical use, and AAFC does not produce parotid pains and hypotension, characteristic side effects of cyclo-C. The main toxicity consists of myelodepression, nausea and vomiting. The schedule dependence of AAFC is far less pronounced than for ara-C, so that a weekly application by rapid i.v. injection of 30-40 mg/kg (1,200-1,500 mg/m2) reaches the level of activity with acceptable toxicity. AAFC seems to be as active as ara-C in acute leukemias and is probably active too in malignant lymphomas. In a large phase II trial of the EORTC on selected solid tumor types, AAFC showed a significant activity in GI tract adenocarcinomas with 2 responses/3 evaluable in pancreas, 7/14 in stomach and 2/32 in colorectal tumors (4/30). Hints of activity were also detected in breast cancer (1/17) and anaplastic small cell carcinoma of the lung (1/9). No responses were obtained in 27 patients with epidermoid carcinoma of the lung. These results confirm that ara-C, or newer ara-C analogs, are potentially active in various solid tumor types, and suggest that an extensive further clinical study of such new derivatives is warranted.