Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026281-06
Application #
3167229
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1978-12-01
Project End
1988-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118