INHIBITION OF DNA REPAIR TO ENHANCE CHEMOTHERAPY

Project: Research project

Project Details

Description

This application is for the continuation of studies to design and develop
inhibitors of O6-alkylguanine-DNA alkyltransferase (AGT) as
chemotherapeutic agents. The presence of AGT is a major factor in the
resistance of tumor cells to killing by drugs that form adduct at the O6-
position of guanine. The aim of these studies is to extend the
effectiveness and the range of tumors that can be treated with these drugs.
Studies during the first period of support have led to Phase I trials with
O6-benzylguanine (BG) but further work is needed to optimize the use of
this agent and to develop compounds with better therapeutic properties in
order to improve the discrimination between tumors and normal tissue.
There are 5 laboratory programs and 3 cores. Dr. A.E. Pegg will serve as
the PI and the Leader of Program 1 which will carry out studies on the
interaction of possible AGT inhibitors with the control and mutant AGT
proteins and design improved inhibitors including compounds able to
inactivate BG-resistant AGTs. Dr. M.E. Dolan will head Program 2 in which
detailed metabolic studies of novel AGT inhibitors will be carried out.
Specific compounds include:metabolism-resistant 8-substituted BG
derivatives; compounds with ester linkages that are activated as AGT
inhibitors by esterases; and benzyl pyrimidine derivatives which are very
potent but rapidly cleared. The use of regional therapy with AGT
inhibitors using intraarterial delivery for CNS parenchymal tumors and
intrathecal administration for leptomengeal neoplasms and the selection of
the most promising compounds for targeting the inhibitor to brain tumors
will be studied in Program 3 led by Dr. H.S. Friedman. Program 4 led by
Dr. S.C. Schold will focus on the development of 9-substituted BG
derivatives including the nucleoside and deoxynucleoside which appear to
offer significant advantages over BG in terms of systemic availability,
penetration of the blood-brain barrier and localized metabolic activation.
Program 5 led by Dr. S.L Gerson will investigate methods for optimizing
tumor cytotoxicity after AGT inactivation. He will study the extent of AGT
inactivation needed to achieve maximal inactivation, methods to overcome
resistance to BG-therapy of colon and breast tumors, and procedures
including gene transfer to minimize bone marrow toxicity of the combination
of AGT inhibitors and BCNU. Routine evaluation of compounds both for AGT
inactivation and for the ability ot sensitize tumor cells in culture to
BCNU will be carried out in Core B led by Dr. Pegg. Promising compounds
will be examined for in vivo pharmacokinetics, tumor AGT inactivation and
sensitization of tumor xenografts in nude mice in Core C led by Dr. Dolan.
StatusFinished
Effective start/end date9/30/969/29/01

Funding

  • National Cancer Institute
  • National Cancer Institute: $737,618.00
  • National Cancer Institute

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