DEVELOPMENT OF DEAZAGUANINE ANALOGS AS ANTICANCER DRUGS

  • Mian, Abdul M., (PI)

Project: Research project

Description

We have described the synthesis and remarkable antitumor activity of
3-Deazaguanine (DG, NSC 261726) and its derivatives. DG in experimental
animal models exhibited highly significant tumor growth inhibitory
properties against a series of slow and rapid growing mammary
adenocarcinomas including those which are used as models for post-operative
breast cancer. DG is activated by HGPRTase and is incorporated into RNA
and DNA. The antitumor properties of DG are believed to be due to the
consequences of its incorporation in DNA. As a result of these studies, DG
is undergoing Phase-1 clinical evaluation. The present studies are aimed
to improve the therapeutic effectiveness of DG either by drug combination
regimens or by the development of its derivatives which will inhibit the
synthesis of DNA specifically. Two sets of drug combination studies
involving DG and Acivicin, and TDG and Acivicin are proposed. The studies
are based on the rationale that: (i) as a result of biochemical effects of
Acivicin, the increased levels of PRPP in tumor tissue will help anabolise
DG and TDG more effectively (as both of these derivatives are activated by
HGPRTase which requires PRPP for activation process); (ii) the inhibition
of nucleotide de novo biosynthesis caused by Acivicin will increase the
reliance of metabolically active tumor tissue on salvage pathway even more
for its survival, thereby promoting the utilization of DG and TDG. The
conditions for optional increase of PRPP, with regard to dose and exposure
time of Acivicin will be established in in vitro and in vivo by assaying
the intracellular PRPP concentrations. Thereafter, the schedules for
combination chemotherapy will be devised to achieve the maximum
potentiation for growth inhibition. Synthesis of 2'-deoxy-3-deazaguanosine
(DGdR) and 6-thio-2'-deoxy-3-deazaguanosine (TDGdR) have been accomplished
with the object to inhibit the synthesis of DNA specifically. DGdR and TDG
have exhibited significant growth inhibitory properties against a number of
transplantable tumors. A comprehensive evaluation of these agents in NCI
recommended panel of tumors is proposed in order to establish the spectrum
and conditions for maximum antitumor effects. The biochemical studies are
proposed in which the effects of these derivatives on macromolecular
synthesis, on nucleotide pool levels and nucleotide interconversion will be
examined in order to establish the mode of action and site of growth
inhibition. Radiolabelled precursor's incorporation and HPLC methodology
will be adopted or developed for these studies. We will also study the
metabolism of these drugs by HPLC procedures where metabolites will be
quantitated and characterized with the help of authentic samples already
prepared in our laboratory.
StatusFinished
Effective start/end date9/1/858/31/89

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

acivicin
Tumors
Derivatives
Pharmaceutical Preparations
Nucleotides
DNA
Tissue
Salvaging
Chemotherapy
Biosynthesis
Drug Combinations
Metabolites
Chemical activation

ASJC

  • Medicine(all)