HALOPYRIMIDINE TUMOR RADIOSENSITIZATION: NEW STRATEGIES

  • Greer, Sheldon, (PI)

Project: Research project

Description

5-Chlorodeoxycytidine (CldC) coadministered with tetrahydrouridine (H4U)
will be utilized to sensitize transplanted murine tumors to X-ray. We have
achieved a 3.4- to 3.8-dose increase effect with X-ray utilizing PALA +
F-pyrimidine treatment prior to CldC + H4U in cell culture. Enzyme
kinetic, DNA incorporation and cell culture studies indicate that C1dC is
converted to CldCMP by deoxycytidine kinade and deaminated by dCMP
deaminase which is markedly elevated (10- to 80-fold) in mouse and human
tumors, to form CldUMP. The 4-amino group protects the nucleoside analog
from catabolism by nucleoside phosphorylases. Thus, we are using a storage
form of a nucleoside analog that we propose is converted preferentially at
the tumor site to a cytotoxic as well as radiosensitizing agent. BrdC can
not be used this way because of its high Km value with respect to dC
kinase. The following are studies which will be undertaken with tumor and
normal tissue of the mouse to determine optimum protocols for the radiation
of transplanted tumors. A. Incorporation of 3H-C1dU derived from 3H-C1dC,
B. Pharmacokinetic and tissue disposition of 3H-C1dC metabolites, C.
Cytokinetic, D. Enzymatic and E. Pool sizes of normal metabolites.
Extensive incorporation studies will be undertaken prior to irradiation of
Sarcoma-180 and Lewis lung carcinoma. Four derivatives of one of these
tumors that are deficient in cytidine- or dCMP-deaminase or deoxycytidine-
or thymidine-kinase will be studied to test the validity of our
hypothesis. We will investigate deleterious effects of C1dC + H4U
administration (e.g. sister chromatid exchange) and, if encountered, we
will rescue by thymidine or deoxycytidine (dC) administration immediately
following radiation. In other approaches to achieve sensitization we will
utilize BrdC or C1dC + low concentrations of H4U in tumors with high levels
of cytidine deaminase. C1dC + 2' dH4U, and inhibitor of dC and dCMP
deaminase, will be utilized to obtain incorporation of C1dC as such into
DNA. Our major strategy goes beyond the exploitation of differences in
cell kinetics between normal and neoplastic tissues; by taking advantage of
quantitative differences in the levels of enzymes, we seek to obtain
preferential conversion of C1dC to C1dUTP at the tumor site. Because the
mechanism of pyrimidine nucleoside radiosensitization is different from
hyperthermy and the action of hypoxic cell radiosensitizers, our approach
may have potential in combination with those modalities.
StatusFinished
Effective start/end date7/1/846/30/87

Funding

  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Deoxycytidine
Neoplasms
deoxycytidine deaminase
NSC 224131
Nucleosides
Tetrahydrouridine
Cell Culture Techniques
X-Rays
Pyrimidine Nucleosides
Cytidine Deaminase
Radiation-Sensitizing Agents
Lewis Lung Carcinoma
Cytidine
Sister Chromatid Exchange
Thymidine Kinase
Cytotoxins
Thymidine
Pharmacokinetics
Radiation
DNA

ASJC

  • Medicine(all)