melphalan and tretazicar

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.

Topics: Animals; Aziridines; Azirines; Colonic Neoplasms; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Interactions; Humans; Lomustine; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Sarcoma, Experimental

CB 1954 potentiates the cytotoxic action of the bifunctional alkylating agent melphalan (L-PAM). In vitro, this potentiation does not require the preincubation in hypoxia normally needed for other nitroaromatic compounds such as misonidazole. Chemopotentiation is observed when cells are held in CB 1954 in air after treatment with L-PAM. This may reflect an inhibition of DNA repair process(es). Structural considerations suggested that CB 1954 might be acting as an inhibitor of poly(ADP-ribosylation). However, an inhibition of the drop in NAD levels consequent on exposure to melphalan was not obtained. Furthermore, unlike the known poly(ADP-ribose) inhibitor, 3-aminobenzamide, CB 1954 does not potentiate the cytotoxicity of the monofunctional alkylator N-methyl-N nitro N-nitrosoguanidine, or inhibit NAD depletion caused by this agent. Therefore the evidence suggests that CB 1954 is not an inhibitor of poly(ADP ribosylation).

Topics: Animals; Aziridines; Azirines; Benzamides; Cell Line; Cell Survival; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Drug Synergism; Melphalan; Methylnitronitrosoguanidine; Poly(ADP-ribose) Polymerase Inhibitors; Radiation-Sensitizing Agents