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Drugs Against Cancer: Stories of Discovery and the Quest for a Cure

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Kurt W. Kohn, M.D., Ph.D.

Dr. Kurt W. Kohn Portrait

Dr. Kohn received an A.B. degree from Harvard in 1952 with majors in Chemistry and Physics, an M.D. degree from Columbia College of Physicians and Surgeons in 1956, and a Ph.D. in Biochemistry and Molecular Biology from Harvard in 1965. After internship at Mount Sinai Hospital in New York, Kohn came to the National Cancer Institute and served as Clinical Associate in the Clinical Pharmacology Service (headed by Paul Condit) 1957-1960. He then spent 2 years as a graduate student and post-doctoral fellow in Paul Doty's laboratory at Harvard, returning to the NCI in 1962 as a member of the Laboratory of Chemical Pharmacology headed by David P. Rall (this Laboratory was a transformation of the earlier Clinical Pharmacology Service).

In 1968, Kohn founded the Laboratory of Molecular Pharmacology (now the DTP) and served as its Chief until 1997. During this time (1961-1997), Kohn's major area of investigation concerned the mechanisms of action of DNA-targeted anticancer drugs. He demonstrated that bifunctional alkylating agents produce DNA interstrand crosslinks and that this is their major cytotoxic action. He elucidated a new mechanism of drug action on DNA, based on the anthramycin group of antibiotics.

In 1974, he discovered the DNA filter elution phenomenon in which DNA molecules pass through micropore filters at a rate dependent on DNA strand length. Based on these observations, he developed methodology to measure several types of DNA damage in mammalian cells. This methodology was widely used for more than 20 years in many laboratories to study DNA damage and repair in mammalian cells. By DNA filter elution studies, Kohn and his colleagues in 1979-1982 showed that DNA topoisomerases are targets of action of several clinical anticancer drugs. This led to worldwide interest in topoisomerase-targeted drugs that has continued to the present time.

In the 1990's, Kohn and his colleagues began to apply the emerging knowledge of cell cycle checkpoints to study the responses of cancer cells to DNA damage. As an aid to this end, Kohn developed a notation for molecular interaction maps that has recently received considerable interest. In 2015, Dr. Kohn became Scientist Emeritus and continues to collaborate and consult on various DTP projects and with other laboratories.


Drugs Against Cancer: Stories of Discovery and the Quest for a Cure

This book may be viewed as a combination of science, history, medicine, and memoir, and hopefully could mostly be understood without a great deal of prerequisite knowledge. Dr. Kohn has tried to give an account of the earliest published work leading to the anti-cancer drug discovery stories that he will relate. The aim of the book was to explain how the knowledge and application of cancer chemotherapy drugs developed. It is in large part a historical account.

Kurt W. Kohn, MD, PhD
Scientist Emeritus
Laboratory of Molecular Pharmacology
Developmental Therapeutics Branch
National Cancer Institute
Bethesda, Maryland
kohnk@nih.gov

Preface and acknowledgements

Introduction

Chapter 1. Anti-cancer drugs that crosslink DNA

Chapter 2. Anti-cancer drugs that attack DNA at a critical site on guanine

Chapter 3. The Platinum Story: From imagination to a major new anti-cancer drug

Chapter 4. Anti-cancer drugs that intercalate between base-pairs in DNA

Chapter 5. The methotrexate story: folic acid analogs

Chapter 6. 5-fluorouracil (5FU): from a simple idea to a major anti-cancer drug

Chapter 7. Analogs of DNA bases and nucleotides become anti-cancer drugs [planned]

Chapter 8. The Story of Doxorubicin: a star with a nearly fatal flaw

Chapter 9. The DNA filter elution story

Chapter 10. Topoisomerase II is a target of anti-cancer drug action

Chapter 11. The camptothecin story: From a "Happy" Chinese Tree

Chapter 12. Anticancer Drugs that Block Cells in Mitosis

Chapter 13. Bleomycin, an anticancer drug with a unique mode of action

Chapter 14. The extraordinary story of the Philadelphia chromosome and a new era of cancer therapy

Chapter 15. The discovery of oncogenes: a foundation for targeted cancer therapy

Chapter 16. Addiction to oncogenes: a conceptual basis for cancer therapy

Chapter 17. The EGFR oncogene story: Addiction to tyrosine kinases; EGFR and HER2 in cancer cause and treatment

Chapter 18. The RAS oncogene story

Chapter 19. The BRAF-melanoma story

Chapter 20. The immunotherapy-melanoma story [planned]

Chapter 21. DNA damage and Repair: Early discoveries

Chapter 22. Genetic diseases reveal DNA nucleotide excision repair

Chapter 23. DNA nucleotide excision repair (NER): cutting out the damage

Chapter 24. DNA base excision repair (BER)

Chapter 25. DNA mismatch repair - colon cancer [planned]

Chapter 26. The homologous recombination and BRCA stories [planned]

Chapter 27. The DNA double-strand break story [planned]

Chapter 28. The gamma-H2AX story: DNA double-strand breaks revealed in cell nuclei

Chapter 29. The ATM and Ataxia telangiectasia [planned]

Chapter 30. The curious case of PARP in DNA repair

Chapter 31. DNA crosslink repair - Fanconi's anemia [planned]

Chapter 32. The APC gene - colon cancer [planned]

Chapter 33. The p53 gene - Li-Fraumeni syndrome [planned]

Chapter 34. Cell cycle control - the RB gene - retinoblastoma [planned]

Chapter 35. DNA repair and cancer therapy [planned]

Chapter 36. drug discovery and development at NCI [planned]


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