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.