The goal of this project is to select an analogue of actinomycin D for evaluation in Phase I clinical trials. Two analogues of AMD, racemic 7-(2,3-epoxypropoxy)- ((plus or minus)-EPA) and N2-(3'-aminopropyl)-AMD (NAPA) demonstrate lower toxicity than AMD and higher activity against murine P388/S, P388/ADR, and L1210 leukemias (previously reported) and solid tumors, B16 melanoma and C26 colon carcinoma. R-(+)- EPA, an enantiomer of (plus or minus-EPA, demonstrates further improved activity in these tumors. To confirm these drugs' broader range of activity, additional tests in Lewis lung (iv), C38 colon, and M5076 (both sc) sarcomas in BDF1 mice and CD8F1 mammary tumor in CD8F1 mice are proposed. The two most active agents will be tested further in human xenografts of lung (LX-1), colon (CX-1) and mammary (MX-1) implanted src nu/nu Swiss mice. With positive results, dose dependent toxicity of the active drugs will be evaluated in mice. The half-lives and metabolism of the radiolabelled drugs in tissues and tumors of mice will be determined; the optimum drug's pharmacokinetic and dose dependent organ toxicity studies will be performed in rats and beagle dogs. With the use of radiolabelled (plus or minus)-EPA and enantiomers, and HPLC technique, adduct formation and metabolite transformation in tumor cells (L1210 and B16) and rat hepatocytes will be investigated. Similar experiments will be performed with NAPA in cells (CHO and V79) and hepatocytes under hypoxia. These results will be compared with the in vitro results derived by use of DNA and hepatic enzymes. Cell lethality by (plus and minus)-EPA and enantiomers and the isoelectronic aziridinyl (AZMA) and cyclopropyl (CPMA)- analogues in clongenic assay (L1210), will be correlated with production of DNA-strand breaks (SSB, DSB, and DPC) in L1210 cells and nuclei using alkaline elution assay.
| 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 |
