The goal of the project is the chemical modification of actinomycin D (AMD) to maximize its therapeutic effectiveness, to broaden its application to a wide spectrum of tumors and to reduce its toxicity in patients. Two effective analogs of AMD, 7-(2,3-epoxypropoxy) - (EPA) and N2-(3'-aminopropyl)-AMD (NAPA) have been synthesized. Both are superior to AMD in therapeutic indices and in the treatment of P388/ADR and L1210 leukemia and exhibit lower toxicity. EPA forms a DNA-adduct in vitro. Elucidation of the pharmacological mode of action of EPA in vivo requires the identification of the adducts in vivo, their rates of formation in liver and cannulated liver of rats, in liver homogenates and with liver enzymes. NAPA is metabolized to an aldehydic metabolite which forms an adduct with protein. Adduct formation of NAPA with DNA in the presence of microsomes or microsomal oxidase enzymes will be studied. Metabolic detoxification of EPA and NAPA which has been indicated by rat urine and tumor homogenate-produced metabolites will be examined using liver, liver enzymes and tumor cells. Biodistribution and toxicity determination and the metabolite formation in rat and in tumor bearing mice will be correlated with inhibition of DNA-synthesis, DNA-fragmentation and the toxicity to tissues and cells. To establish a broader spectrum of activity, the analogs and their active metabolites will be tested in B16 melanoma, Lewis lung carcinoma and colon carcinoma 38 in mice.
| Sengupta, S K; Rosenbaum, D P; Sehgal, R K et al. (1988) Enantiomers of 7-(2,3-epoxypropoxy)actinomycin D as dual-action DNA-acting antitumor agents. J Med Chem 31:1540-7 |
| Sehgal, R K; Almassian, B; Rosenbaum, D P et al. (1988) Synthesis and biological properties of actinomycin D chromophoric analogues substituted at carbon 7 with aziridine and cyclopropyl functions. J Med Chem 31:790-3 |
| Sehgal, R K; Almassian, B; Rosenbaum, D P et al. (1987) Synthesis and biological properties of actinomycin D chromophoric analogues substituted at the 7-carbon with aziridine and aminopropoxy functions. J Med Chem 30:1626-31 |
