Cancer Therapy Series:

1. Cancer Therapy Series: Alternative Cancer Therapies

2. Cancer Vaccines The way a vaccine works: Introduce an antigen into a host in a small dose. Initiate host system into an immune response to antigen. Body will attack any cell producing this antigen in the future. Requires cancer cells to produce an antigen distinct from normal cells…

3. Cancer Vaccines Not used as a preventive measure, used as a treatment. Previous methods just injected antigens into a host, personalized vaccines exist as well. New method currently in phase III trials by Dendreon. New method uses the dendritic cells to initiate a T-cell immune response directly.

4. Cancer Vaccines So, what IS the antigen? Nearly all advanced prostate cancer cells express Prostatic Acid Phosphatase (PAP) almost exclusively. Dysfunctional prostates release PAP into the blood, making it a good test marker. Normal PAP is found in prostate and semen. PAP wasn’t enough, researchers realize it’s a fusion protein with PAP and a cytokine called granulocyte-macrophage colony-stimulating factor (GMCSF), which must be recognized for immune response to engulf and properly flag the cancer cell for destruction.

5. Cancer Vaccines

6. Monoclonal Antibodies How this works: An animal is vaccinated against a particular antigen, its B-cells/antibodies are then harvested. Monoclonal antibodies are very specific, there is no difference in their variable regions.

7. Monoclonal Antibodies Research has been done on monoclonal antibodies since the 1970’s, but research can be difficult because: Mouse cells are used to make the antibodies, and the immune system recognizes them as foreign and removes them. Antibodies can react with antigens in the body found on normal as well as cancer cells, so there can be some side effects.

8. Monoclonal Antibodies Immunologist Ron Levy of Stanford Medical Center first reported using custom antibodies to attack a lymphoma in his patient, Philip Karr, in 1982. Many subsequent trials on different cancers did not match the results in mouse, however, and some patients were even killed from toxicity effects. Interest in antibody cancer therapies rekindled as recent research has yielded some positive results. Among the problems addressed were making mouse cells unrecognizable by the human immune system (humanization) and working to create a response without side effects.

9. Monoclonal Antibodies Two methods have been used to destroy the cell, once it’s successfully targeted. The earlier of the two ways relied only on the body’s immune system to recognize an antibody and destroy its tagged cells. Another method uses antibodies to target something toxic to specific cells. A recent method with some promise involves nanotechnology: Actinium-225 (225Ac) carries a 10 day half-life and decays via alpha radiation through three atoms. A single molecule of 225Ac is coupled to a delivery vehicle and antibody, termed 225Ac-DOTA-antibody, which is then delivered to a target cell.

10. Phytochemicals “[Long known] that diets high in fruits, vegetables, grains and legumes appear to reduce the risk of … cancer when compared with diets high in meat.” (Balch and Balch, 1997) Recently attributed to antioxidants, but researchers are learning more about a new group of health-promoting nutrients called phytochemicals.

11. Phytochemicals Phytochemicals are plant proteins that are biologically active: They are responsible for a plant’s color, flavor and natural disease resistance. Not required for healthy living, but may provide some added health benefits. Not really a cancer treatment, but seem to be very effective for preventing cancer.

12. Phytochemcials Phytochemicals appear to work by blocking one or more of steps that lead to cancer. Example: Sulforaphane is a phytochemcial found in broccoli. If it reaches a cell before a carcinogen, it will activate a set of enzymes that will eliminate the carcinogen before it can do any harm. Example: Flavonoids (citrus fruits, berries) prevent cancer-causing hormones from latching onto cells in the first place. Example: Genistein (soybeans) kills tumors by preventing capillary formation.

13. Phytochemicals Many phytochemicals are constantly being found; over 10,000 believed to be in tomatoes alone! Available in concentrated, pill form, though recommended against. Starting to receive a lot of scientific attention, as with a recent study of lycopene on breast cells proteins BRCA1 and BRCA2 (Chalabi et al. 2004).

14. Gene Therapy Tissue Specificity Clear Benefits for Cancer Treatment Regulation of gene expression Ability to repair dysfunctional cells Easily administered Injection, aerosol application

15. How it works Introduce genes that can correct a cancer cell’s dysfunction (tumor-suppressor protein, pro-apoptotic protein) RNA can also be targeted

16. Delivery Viral Vectors Retro viruses, adenoviruses, herpes simplex Non-Viral Liposomes, cationoic polymers Physical Disruption of Membrane

17. Retroviral Vectors Only Transduce dividing cells (easy targeting) Undergo reverse transcription, then integrate into the genome Concerns with DNA integration

18. Tissue – Specific Targeting Gene promoters can include sequences that restrict transcription to certain tissues/cell types Several promoters have potential as targeting sites for cancer, particularly in prostate tissues

19. Thermosensitization Heat can be used in conjunction with other therapeutic methods to improve the elimination of tumor cells Thermochemotherapy (Use of hypothermia with chemo) has been shown to increase the effect of chemotherapeutic drugs

20. MMC – an Antitumor Antibiotic Mitomycin C (MMC) Crosslinks with DNA, inhibiting synthesis and division. Effects of MMC often result in cell death. Used as a chemotherapeutic agent

21. Hypothermia and MMC have a Synergistic Effect Cell Temperature is raised to at least 40ºC Both heat alone, and MMC alone display the ability to destroy mutant cells. When the treatments are combined, the effect is much greater

22. Treatment Response of p53 mutants O – Heat alone - MMC alone - Heat and MMC

23. Possible Explanations Hypothermia induces cellular uptake of MMC (affects membrane permeability) May enhance the DNA crosslinking capabilities of MMC

24. Even mild hypothermia (42ºC) demonstrates a significant change in cell death, making this a promising method to improve chemotherapy

25. References Tom’s References: P53-independent thermosensitization by mitomycin c in human non–small-cell lung cancer cells*1 Zhao-Hui Jin M.D., Ph.D.*, Hideki Matsumoto Ph.D. , , *, Sachiko Hayashi Ph.D.*, Masanori Hatashita Ph.D.*, Toshio Ohtsubo M.D., Ph.D.†, Hiroki Shioura M.D., Ph.D.‡, Ryuhei Kitai M.D., Ph.D.§ and Eiichi Kano M.D., Ph.D.* International Journal of Radiation Oncology*Biology*Physics Volume 59, Issue 3 , 1 July 2004, Pages 852-860 Gene-based therapy in prostate cancer Ruth Foleya, Mark Lawlerb and Donal Hollywood The Lancet Oncology Volume 5, Issue 8 , 1 August 2004, Pages 469-479 Jonny’s References: Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. 2002 Molecular Biology of the Cell. Garland Science, Taylor & Francis Group, New York. Chen, A. Dendritic Cell Image. 2004. Scientific American. July. Balch J. and Balch P. 1997. Prescription for Nutritional Healing: a practical Ato Z reference to drug-free rememdies using vitamins, minerals, herbs & food supplements. Avery Publishing Group, New York. Jakob, C.G., Lewinski, K., Kuciel, R., and Ostrowski, W. Crystal structure of PAP molecule, chain a, b, c, d. PDBsum <http://www.biochem.ucl.ac.uk/bsm/pdbsum/1cvi/main.html> McDevitt, M.R., Ma, D., Lai, L., Simon, J., Borchardt, P., Frank, R.K., Wu, K., Pellegrini, V., Curcio, M.J., Miederer, M., Bander, N., Scheinberg, D.A. 2001. Tumor Therapy with Targeted Atomic Nanogenerators. 294: 1537-1540. No author given. Monoclonal Antibody Production Protocol. Perez Homepage, Natural Toxins Research Center. Texas A & M University, Kingsville. <http://ntri.tamuk.edu/monoclonal/overall-map.html> No Author Given. 2002. Immunotherapy. Cancer Research UK. <http://www.cancerhelp.org.uk/help/default.asp?page=129> Shulman, M., C.D. Wilde, and G. Kohler. 1978. A better cell line for making hybridomas secreting specific antibodies. Nature 276: 269-270 Stix, G. 2004. Overcoming Self. Scientific American. July. Review Article. Wardlaw, G. 2000. Contemporary Nutrition: Issues and Insights. McGraw-Hill, Boston and other places.