Biochemical Modulation of Anticancer Agents: Experimental and Clinical Approaches

1. Front Matter

   Pages i-xvii

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2. Biochemical Modulation of Anticancer Agents: An Overview

   • Randall Johnson, Fred Valeriote

   Pages 1-21

3. Biochemical Loci for Modulation of 5-Fluorouracil Activity

   • Peter V. Danenberg

   Pages 23-42

4. Biochemical Modulation of 5-Fluorouracil with Pyrimidines, Purines and their Nucleosides

   • Giovanni Santelli

   Pages 43-64

5. Biochemical Modulation of Pyrimidine Pools for Enhancement of Antipyrimidine Cytotoxicity

   • Daniel S. Martin

   Pages 65-91

6. Modulation of 5-Fluorouracil Cytotoxicity by Intracellular Pools of 5-Phosphoribosyl-1-Pyrophosphate (PRPP)

   • C. Benz, R. Heimer, E. Cadman

   Pages 93-105

7. Biochemical Rationale for Selectivity in the Modulation of Methotrexate Activity During Leucovorin Rescue or Early Nucleoside Protection

   • I. David Goldman, Larry H. Matherly

   Pages 107-129

8. Clinical Aspects of FUra Metabolism

   • Brian Leyland-Jones, Peter J. O’Dwyer

   Pages 131-152

9. Metabolic Modulation of Ara-C

   • Youcef M. Rustum, Joel Campbell

   Pages 153-170

10. Enhancement of Alkylating Agent Cytotoxicity by Radiation Sensitizers

    • J. Martin Brown, David G. Hirst, Michael R. Horsman, Yvonne C. Taylor

    Pages 171-189

11. Modulation of Alkylating Agents by Radiation Sensitizers— Clinical Aspects

    • Cary A. Presant

    Pages 191-203

12. The Role of Cellular Glutathione in Response of Tumor Cells to Radiation and Drugs

    • John E. Biaglow, Marie E. Varnes, Edward P. Clark, Edward R. Epp

    Pages 205-244

13. Modulation of Intracellular Levels of Glutathione

    • Alton Meister

    Pages 245-275

14. Glutathione Depletion with Buthionine Sulfoximine: Potential Clinical Applications

    • Robert F. Ozols, Thomas C. Hamilton, Karen G. Louie, Brent C. Behrens, Robert C. Young

    Pages 277-293

15. Modification of Cell Sensitivity to Anticancer Agents by Polyenes

    • Guy G. Chabot, Frederick A. Valeriote

    Pages 295-323

16. Modulation of the Efflux of Anticancer Agents

    • Ta-hsu Chou

    Pages 325-341

17. Problems in the Clinical Evaluation of Biochemical Modulation Therapy

    • Laurence H. Baker

    Pages 343-350

Biochemical Modulation at the present time defines an area of study in which the intracellular metabolism of a given anti­ cancer agent is modulated (usually by a noncytotoxic agent or a cytotoxic agent at sufficiently low dosage to make it non­ cytotoxic) in order to either increase the effectiveness of the particular agent against tumor cells or decrease its cytotox­ icity against normal cells. The major focus of modulation has been the agents 5-fluorouracil (FUra), arabinofuranosylcytosine (ara-C), methotrexate (MTX) and a few alkylating agents. The major thrust of the studies has been to increase the flow of the anticancer agent along the pathway responsible for the formation of the cytotoxic species: for example, FUra to FUTP or ara-C to ara-CTP. While in most cases the application of research re­ sults to clinical trials does not require the subsequent exper­ tise of the laboratory researchers, application of biochemical modulatory schemes to clinical protocols necessitate a dramatic break with the past procedures. As shown in the laboratory­ clinical loop below, close collaboration between the laboratory and clinical investigator is essential. While the laboratory REDEFINE TECHNOLOGY, TESTS OR QUESTIONS FOR FURTHER THERAPEUTIC ADVANCE CLINICAL EXPERIMENTAL PROTOCOL (LABORATORY) RESEARCH STUDIES DEFINE AND TEST APPROPRIATE SCIENTIFIC PARAMETERS results define rationally-based regimens, it is essential that the clinical protocols contain the requirement that clinical material (either tumor or normal tissues) be sampled to deter­ mine whether the biochemical modulation being proposed is in fact beinq accomplished.

• Purine
• Pyrimidine
• cell
• clinical trial
• metabolism
• tumor

`As a whole this book is a useful reference in a relatively new field of cancer research that may eventually expand the scope of cancer chemotherapy.'
Adverse Drug Reaction, Vol. 7, No. 1, Spring 1988

• Wayne State University School of Medicine, Detroit, USA

  Frederick A. Valeriote, Laurence H. Baker

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