NOVEL APPROACHES TO ANTITUMOR DRUG DEVELOPMENT

The proposed research in this NCI Outstanding Investigator Grant
includes a description of ongoing projects funded through CA-30349
and CA-35318 and a new project entitled "Template directed design
synthesis of novel DNA reactive drugs." The overall objectives of the proposed research are to: (1)
provide a new rationale for the development of more clinically
effective antitumor drugs, (2) rationalize the biochemical and
biological effects of DNA modification on the basis of the effects
of drug-binding on the structural and dynamic properties of DNA. The specific objectives of the proposed research are to: (1)
determine the effects of drug-binding on local DNA structure and
dynamics, (2) determine the structural and/or dynamic features
which lead to repair recognition of damaged DNA, (3) determine the
effect of drug binding on transcriptional control in eucaryotic
systems, (4) isolate and identify novel drug receptors, and (5)
design and synthesize new DNA-reactive drugs using a DNA template
directed approach. States simply, the overall problem we propose to tackle is to
elucidate the molecular basis for the antitumor activity of CC-1065
and the P(1,4)Bs. This problem is broad in context and requires
an interdisciplinary approach, using a variety of physical and
biochemical techniques. A central theme of our studies aimed towards determining the
molecular basis for antitumor activity of CC-1065 and the P(1,4)Bs
is to relate the structural changes in local DNA structure induced
or entrapped by these drugs to the biochemical and biological
effects. One aspect of the proposed work is to determine drug-
related changes in DNA structure and relate these to the observed
asymmetric effects on DNA structure, the origin of drug induced
bending in DNA, and the molecular basis for the DNA sequence
specificity of these agents. Further studies are proposed to
identify DNA binding proteins involved in mediating the potent
biological effects of the compounds.