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Potentiation of the Cytotoxic Action of Mafosfamide by N-Isopropyl-p-formylbenzamide, a Metabolite of Procarbazine¹

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

Several mouse aldehyde dehydrogenases catalyze the detoxification of aldophosphamide, the pivotal metabolite of the prodrugs cyclophosphamide, mafosfamide, and other oxazaphosphorines. N-Isopropyl-p-for-mylbenzamide, a major metabolite of procarbazine, was found to be an excellent substrate (K_m = 0.84 µM) for at least one of these enzymes, namely, mouse aldehyde dehydrogenase-2. The K_m for mouse aldehyde dehydrogenase-2-catalyzed detoxification of aldophosphamide is 16 µM. Thus, competition between N-isopropyl-p-formylbenzamide and aldophosphamide for the catalytic site on the enzyme should strongly favor the former, and the rate at which aldophosphamide is detoxified should be markedly retarded. Mouse L1210/OAP and P388/CLA leukemia cells are relatively insensitive to the oxazaphosphorines because they contain large amounts of mouse aldehyde dehydrogenase-2. As predicted, N-isopropyl-p-formylbenzamide markedly potentiated the cytotoxic action of mafosfamide against these cells. Mouse L1210/0 and P388/0 lack the enzyme. Again as expected, N-isopropyl-p-formylbenzamide essentially did not potentiate the cytotoxic action of mafosfamide against these cells. Certain mouse and human hematopoietic progenitor cells also contain an aldehyde dehydrogenase that catalyzes the detoxification of aldophosphamide, but the specific identity of this enzyme remains to be established. N-Isopropyl-p-formylbenzamide potentiated the cytotoxic action of mafosfamide against these cells as well. Clinically, procarbazine and the oxazaphosphorines are used to treat certain neoplastic diseases. Frequently, they are used in combination. Our findings demonstrate the potential for both desirable and undesirable drug interactions when these agents are used concurrently. Similar drug interactions can be expected when other substrates for, or inhibitors of, the relevant aldehyde dehydrogenases, e.g., chloramphenicol, chloral hydrate, and methyltetrazolethiol-containing cephalosporins, are co-administered with the oxazaphosphorines.

¹ Supported by USPHS Grant CA 21737. A description of parts of this investigation has appeared in abstract form (41).

² Present address: Department of Radiation Oncology, Division of Oncology Research, University of Pennsylvania, 530 Clinical Research Building, 422 Curie Boulevard, Philadelphia, PA 19104-6142.

³ To whom requests for reprints should be addressed, at the University of Minnesota, Department of Pharmacology, 3-249 Millard Hall, 435 Delaware Street S.E., Minneapolis, MN 55455.

Received 2/ 1/91. Accepted 6/ 3/91.