Caracemide

Abstract: Twenty-four previously untreated, ambulatory patients with advanced colorectal carcinoma were treated with either caracemide (11 patients) or homoharringtonine (13 patients). No objective responses were observed in any of the treatment cohorts. Caracemide was well tolerated with the exception of one death due to sepsis. On the homoharringtonine arm one patient died of pulmonary sepsis, one patient experienced grade 4 leukopenia requiring more than 4 weeks of recovery, and an additional patient developed grade 4 renal failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced colorectal carcinoma.

Abstract: Forty-eight previously untreated, ambulatory patients with advanced or unresectable renal carcinoma were treated with either amonafide (17 patients), caracemide (17 patients), or homoharringtonine (14 patients). No objective responses were observed in any of the treatment cohorts. Amonafide and caracemide were well tolerated with no unexpected toxicities. One patient each died of pulmonary thromboembolism and sepsis with severe metabolic acidosis on the homoharringtonine arm. An additional 4 patients experienced grade 4 complications including myelosuppression, neurologic dysfunction, and respiratory failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced renal cell carcinoma.

Abstract: Part 1 Control of cancer by amino acid analogs, G.S. Ahluwalia et al: azaserine. Part 2 Metabolism of pyrimidine analogues and their nucleosides, G.C. Daher et al: fluoropyrimidines azacytidine. Part 3 Metabolism and action of purine nucleoside analogs, W. Plunkett and P.P. Saunders: tiazofurin neplanocin A. Part 4 The basis for antifolate cytotoxicity, selectivity and metabolic transformation - effects on utilization of endogenous and exogenous folate cofactors, L.H. Matherly et al: mammalian folylpolyglutamate synthetase. Part 5 The metabolic basis for combination chemotherapy, L.E. Damon and E.C. Cadman: synergistic modulation. Part 6 The metabolism of antihormonal anticancer agents, S.P. Robinson and V.C. Jordan: treatment strategies for hormone-dependent cancers antiestrogens. Part 7 Metabolism of natural and synthetic steroids used in cancer treatment, R.Y. Kirdani et al: metabolism of natural and synthetic androgens used in cancer therapy. Part 8 Metabolism of plant-derived anticancer agents, G. Cragg and M. Suffness: bruceantin taxol. Part 9 Metabolism of protein anticancer agents, V. Bocci: cytotoxins tuftsin. Part 10 Metabolism of new anticancer agents, Z.H. Siddik and R.A. Newman: caracemide trimelamol flavone acetic acid hycamptamine sulofenur. Part 11 Metabolism of cancer drugs as a basis for drug resistance, S. Kuzmich and K.D. Tew: glutathione S-transferases - structure and function future perspectives. (Part Contents).

Abstract: Following administration to rats of a single ip dose (6.6 mg kg-1) of the investigational antitumor agent caracemide (N-acetyl-N,O-bis[methylcarbamoyl]hydroxylamine), the mercapturic acid derivative N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) was identified in urine by thermospray LC-MS. Quantification of this conjugate was carried out by stable isotope dilution thermospray LC-MS, which indicated that the fraction of the caracemide dose recovered as AMCC in 24-h urine collections was 54.0 +/- 5.5% (n = 4). Since AMCC is known to represent a major urinary metabolite of methyl isocyanate (MIC) in the rat, the results of this study support the contention that caracemide yields MIC as a toxic intermediate in vivo. Furthermore, with the aid of a specifically deuterium-labeled analog of caracemide ([carbamoyloxy-C2H3]caracemide), it was shown that the methylcarbamoyl group of AMCC derived from both the O-methylcarbamoyl (72%) and N-methylcarbamoyl (28%) side chains of the drug. In view of these findings, it is concluded that caracemide acts as a latent form of MIC in vivo and that this reactive isocyanate (or labile S-linked conjugates thereof) may contribute to the antitumor properties and/or adverse side-effects of caracemide.