Basis and new developments in the field of oxazaphosphorines.
All the research results summarized herein were gained in the attempt to improve selectivity in cancer chemotherapy: "Chemotherapeutic agents are not only ends in themselves, they are also beginnings,. . . Selectivity must be our goal and understanding its basis our guide to the future" (138). The development of the OAP cytostatics CP, IFO, TRO, and SUFO derives from the idea of applying the principle of transport form/active form to the highly reactive nitrogen mustard compounds. The desired conversion of the reactive nitrogen mustard into an inactive transport form (latentiation) was performed by chemical synthesis. The requirement for an enzymatic activation of the transport form to give the active form in the target organ cancer cell was met and has been shown to occur in a sequence of various metabolic reactions. The goal of a substantial increase in the therapeutic range of alkylating agents has been achieved with the development of the OAP cytostatics. The higher cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. A further increase in the cancerotoxic selectivity in OAPs was achieved by the development of mesna as a regional uroprotector. Mesna eliminates the danger of therapy-limiting urotoxic side effects of OAPs, allowing administration of higher dosages and more safely optimizing their therapeutic efficacy and partly overcoming resistance phenomena. The stabilization of the primary OAP metabolites (MAFO), opens up new possibilities in clinical therapy and in preclinical tests, for examination in the clonogenic stem cell test, for in vitro purging in ABMT, and for the regional therapy of tumors. A completely new type of therapy is emerging for OAP, specifically for low-dosage MAFO, as an immunomodulator, under certain circumstances, in combination with further substances, from the biological response modifier group.
Brock
N
N
Department of Cancer Research, ASTA PHARMA AG, Bielefeld, Federal Republic of Germany.
Hilgard
P
P
Peukert
M
M
Pohl
J
J
Sindermann
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D010752:Phosphoramide Mustards; D011355:Prodrugs; C048341:mafosfamide; D003520:Cyclophosphamide; D007069:Ifosfamide