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Of Mice and Men: The Art and Science of Finding, Making, and Testing Anti-Tumor Agents

Of Mice and Men: The Art and Science of Finding, Making, and Testing Anti-Tumor Agents. William A. Price, Ph.D. Department of Chemistry & Biochemistry Sponsored by C.A.R.E. Chymian Society. Number of Deaths/100,000 in U.S.A. Year Heart Disease Cancer 1950 590 195

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Of Mice and Men: The Art and Science of Finding, Making, and Testing Anti-Tumor Agents

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  1. Of Mice and Men:The Art and Science ofFinding, Making, and TestingAnti-Tumor Agents William A. Price, Ph.D. Department of Chemistry & Biochemistry Sponsored by C.A.R.E. Chymian Society

  2. Number of Deaths/100,000 in U.S.A. Year Heart Disease Cancer 1950 590 195 1970 490 200 1990 410 210 2002 240 200 Since 1950: Heart disease rates cut by 59% Stroke rates cut by 69% $200,000,000,000 spent since 1970 for cancer research

  3. Care to Smoke? • 87% of lung cancers and 30% of all cancers are due to smoking. • 438,000 people die each year in the U.S. as a result of smoking. • Half of all smokers will die prematurely – half of those will die of cancer. • Smoking causes reduced fertility in women, together with higher risks of miscarriage, still-birth and low birth weight.

  4. A Public Health Issue • In the Year 2000, the CDC estimates that 8.6 million people were suffering from chronic illnesses due to smoking. • Addiction to nicotine, a CNS stimulant, significantly contributes to the public health problem.

  5. Nicotine mimics Acetylcholine • Activates neurological reward pathways similar to cocaine and MDMA • These cholinergic pathways are artificially stimulated and cause an unnatural release of dopamine (pleasure) thus causing a need for more of these “pseudo-neurotransmitters”. Biochemical addiction

  6. What is Cancer? • Develops from a single cell that has undergone a genetic mutation • Rapid, unregulated cell division is stimulated by a combination of genetic and environmental influences. • Begins locally and usually spreads through lymph nodes – metastasis • There over 150 different types of cancer.

  7. What is an Anti-Tumor Agent? • Toxic compound that can penetrate a cell wall, • Can disrupt the physiology and/or chemistry of DNA in order to prevent cell replication by either: • covalently and irreparably binding to DNA • inhibiting enzymes or proteins responsible for pre-mitotic DNA unraveling • causing hyper-coiling of chromatin around histones by affecting phosphorylation or acetylation • cutting off blood supply to tumors (angiogenesis)

  8. Ideally… Antitumor agents are: • non-toxic to healthy cells, • are particularly toxic to rapidly-dividing cells • delivered safely (e.g. IV, injection, organ-targeted pill) and preferably to the afflicted cells.

  9. Weed Killer and Rat PoisonTrisenox • As2O3 is still used to treat acute promyelocytic leukemia, APL, a cancer of the bone marrow due to a chromosomal translocation. • Patient receives roughly 60 daily injections of ~10mg doses over a period of 2 months. • Side effects include suppressed immune system, heart irregularities, internal bleeding, high blood pressure,confusion, fainting, dizziness, eye pain, blurred vision, excessive weakness, excessive fatigue, or excessive drowsiness. Yikes!

  10. How do We Find Cancer Drugs? • We take a cue from Nature. • Compounds found in plants, mold, bacteria, algae, some insects, marine mammals and even snake venom are often excellent growth inhibitors. • From the Pacific Yew tree, some 300 different organic compounds were isolated and characterized and tested.

  11. From the Bark of the Pacific Yew Tree

  12. How Taxol Works • A large number of microtubules are formed at the start of cell division, and as cell division comes to an end, these microtubules are normally broken down into tubulin – a protein responsible for the cell’s structural stability. • Taxolbinds to the microtubules and inhibits their depolymerization into tubulin. • The cell can't divide into daughter cells and therefore the cancer can’t spread.

  13. Tubulin with Taxol bound to one of the Functional Domains

  14. Taxol Causes Cells’ Tubulin Skeleton to Aggregate in Spindles

  15. May be More Effective than Taxol

  16. DNA Cross-linker

  17. Replication

  18. Prevents DNA from Unraveling

  19. Radiosensitizationand Chromatin Compaction • At FCCC, our group studied the effects of compounds that affected a cell’s chemistry by inhibiting enzymes that allow for specific chemical reactions to occur. • Without these reactions occurring, the DNA in the cells tended to hyper-coil around proteins called histones. Compacted Chromatin • With a preponderance of our cancer cells now hypercoiled, they presented an unusually dense target for ionizing radiation. Hence these cells were radiosensitized.

  20. FR 901228Histone Deacetylase Inhibitor

  21. A RadiosensitizerProtein Phosphatase Type 1 and 2a Inhibitor

  22. Two Phosphatase Inhibitors

  23. Animal Models Researchers use SCID mice onto which human tumors can be xenografted.

  24. Thank You! • J.D. Chapman, R. Schneider, C. C. Stobbe • Fox Chase Cancer Center • CHM 320 class • Michael Prushan, Ph.D. • National Institutes of Health (#CA06927) • La Salle University

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