Enhancement by electron-affinic agents of the therapeutic effects of cytotoxic agents against the KHT tumor: structure-activity relationships.

We have studied the effectiveness of various electron-affinic and other modifying agents on the in vivo response of the KHT sarcoma to various cytotoxic agents. Misonidazole (MISO) showed good enhancement with CCNU, methyl-CCNU, BCNU and chlorambucil (CHL), a small enhancement with cyclophosphamide (CYC), but none with melphalan or HN2. With CYC a further small enhancement was obtained with a multiple-dose pretreatment, but host toxicity was also increased. Lipophilicity was more important than electron-affinity for CCNU enhancement. Several lipophilic analogues (e.g. benznidazole and Ro 07-1902) gave enhancements superior to MISO, whereas hydrophilic analogues were inferior. Similar results were obtained with CHL. Enhancement of CCNU response was seen with the nitrofuran, nitrofurantoin, and the quinone, anthraquinone sulphonate. The non-electron affinic compound imidazole gave enhancement with CHI, but not with CCNU. The inhibitor of drug-metabolizing enzymes SKF 525A gave excellent enhancement with both CHL and CCNU.