1. Folder Title: CxChemoPart1
Cancer Chemotherapy Part I: General Cancer Chemotherapy Chapter 16; Pages 797 to 815A also Section 16.11: Drug Resistance
Folder Title: CxChemoPart1
Updated: May 1, 2017

2. Therapeutic Modality Options
Surgery
Radiation: X-Ray; Photodynamic Therapy; Thermal Ablation; Microwave;
Chemotherapy (Including Hormonal Therapy)
See Chapter 16: Rational Treatment of Cancer
Immunotherapy See Chapter 15: Crowd Control – Tumor Immunology and Immunotherapy
Host Response Modification
Gene Therapy (and Virotherapy?)
“Specific-Targeted” Therapies: Monoclonal antibodies or pharmaceuticals directed to errors in signaling pathways, to signal receptors, or to other key oncoproteins or suppressor proteins.

3. Combined Modality Therapies for Cancer
Surgery and Radiation
Adjuvant Chemotherapy: Surgery and Chemotherapy
Radio-sensitizers: Chemotherapy and Radiation
Chemotherapy and Host-Response Modification
Hormones and cytokines in Cancer Chemotherapy
Induction of Differentiation by Chemotherapeutic Agents
Induction of Apoptosis by Chemotherapeutic Agents
Immunotherapy and Gene Therapy
Genetically Engineered T-Cells
Chemotherapy with Ultra-sonic Disruption?

4. Cancer Treatment Problems
Diagnosis and Prognosis: Will This Cancer be a Problem? How do we know what to expect?
What are the side effects of treatment likely to be?
Is treatment worth it for the patient?
What are the costs to the patient and to society?
How do we make treatment options fairly available?
Within the United States
Around the World?

5. Cancer Chemotherapy: How Are We Doing?
Lung Cancer 5 Year Survival %
Lung Cancer 5 Year Survival %
The Effect of Earlier Diagnosis. How Much Real Progress is There?
Show Presentation Folder Title:
Under Cancer War: Cancer Research the 90Billion Metaphor

6. Magnetic Resonance Imaging (MRI) of Breast Cancer
Will this become a problem?
Should we let it alone?
How can we tell?

7. 67% of Women have breast cancer at autopsy after death from other causes by age 80.
4% of women die of breast cancers.
Which breast cancers do we treat?
Which do we monitor and not disturb?
Increased incidence
Better diagnosis?
More screening?
Changes in behavior, obesity, reproductive behavior, diet?
Declining mortality after 1994

8. How Can We Tell Who to Treat?
Who is really at highest risk?
Which patients do we not know how to help?

9. 295 Patients
( )
115 had low mets
14/115 = 12%
180 had high mets:
75/180 = 42%
70 Genes analyzed for expression.
Green = suppressed
Red = Amplified

10. Declining Death Rates
No real improvement of treatment effectiveness

11. Two Turning Point Questions

12. What is this graph telling us about prevention and/or treatment of these cancers from 1950 to 1990?
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13. What was done to produce the reduction in breast cancer dimensions between these two magnetic resonance images?
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14. A Success Story: Testicular Cancer Prior to 1965: 10% Survival
The discovery of cis-platinum: bifunctional alkylating cross-linking agent
Chemotherapy by Chemical Damage to DNA of Dividing Cells

17. Aminopterin (Methotrexate) First Chemotherapeutic Cancer Cure: 1947
Inhibits Nucleotide and Therefore DNA Synthesis in Dividing Cells Like Leukemia Cells
Chemotherapy of inhibiting DNA synthesis of dividing cells

20. How Do We Get Specificity or at Least Selectivity for Cancer Cells in Preference to Normal Cells?
See Next Slide
See Slide 40 for Therapeutic Index

21. (See Figure 12-40 and Sidebar 12.11, p. 520 Weinberg)
Chemotherapy Directed Toward Defective BRCA-1 and BRCA-2 Genes in Breast and Ovarian Cancers
(See Figure and Sidebar 12.11, p. 520 Weinberg)
Propositions:
Redundant DNA-repair mechanisms needed by both normal and neoplastic cells to repair DNA lesions incurred normally during cell division.
One type of DNA repair involves poly-ADP-ribose polymerase (PARP).
BRCA-1 and BRCA-2 have DNA repair functions as “Housekeeping genes”.
Normal cells can use BRCA-1 and BRCA-2 repair functions as well as PARP repair mechanisms.
Breast and Ovarian cancer cells with functional BRCA-2 genes can still repair DNA even if their PARP repair is blocked.
For breast cancer cells that lack a copy of the BRCA-2 repair gene, they have to use the PARP repair pathway.
What happens if one inhibits the PARP repair function using PARP inhibitors, especially when treating the patient with chemotherapeutic agents that damage DNA?

22. Figure Weinberg
Cells lacking BRCA-2 (red line) are killed off (2 log kill or 99% kill) at 10E-7 M (0.1 uM) anti-PARP drug concentration. (The structure of the inhibitor is not specified).
Cells with BRCA-2 repair (blue or green lines) can survive almost 1,000-fold higher concentration of anti-PARP agent (10E-4M or 100 uM) because they can use BRCA-2 for DNA repair.
90% Cell Kill
“PARP” = Poly-ADP-Ribose Polymerase (DNA Repair Mechanism; alternative to BRCA-2 DNA-Repair Mechanism)
Anti-PARP
Ended here Class 27, April 27th, 2017)

23. Cell Cycle-directed Cancer Chemotherapy

24. Attacking Cycling Cells: Cell-cycle Directed Anti-neoplastic Drugs
Cell Cycle Phase
Drug
Target
Go – G1
Taxol
Microtubules (stabilize)
S-Phase
Ara-C (Cytosine arabinoside)
DNA synthesis
S- G2
VP-16 (Etoposide)
Topoisomerase II M
Vinca-alkaloids
Microtubule disrupters
Microtubule stabilizer
Non-cell-cycle specific
Alkylating agents:
Cis-platinum
Cyclophosphamide
Nucleophiles (e.g. DNA)

25. Cell Cycle Specific Agents in Cancer Chemotherapy
Cell cycle specific anti-cancer agents
Pitot, Figure 20-13

26. Host Response Modification in Cancer Chemotherapy:
Tissue-Specific Trophic Factors (Cytokines, Growth Factors, Hormones),
their tissues of origin, and their target tissues
Trophic Factor
Target Tissue
Tissue of Origin
Testosterone
Prostatic Epithelium
Testes
Estrogen
Mammary and Uterine Epithelium
Ovary
G-CSF*
Neutrophil Progenitors
Interleukin-3
Myeloid Progenitors
Mpl Ligand
Platelet Progenitors
Erythropoietin
Erythroid Precursors
Interleukin-2
Lymphocytes
Kidney
Interleukin-4
*G-CSF = Granulocyte Colony Stimulating Factors

27. Combination Chemotherapy:
What if we combine Anti-cancer Drugs Working by Different Mechanisms?

28. Physician’s Desk Reference Multitude of Agents to Choose From
Oncology Reference Guide
203 Oncology Treatment Agents
Published in 2003
How are We doing?

29. Why Can’t We do Better in Terms of Cancer Treatment?
We Have Over 200 Agents Now
Why Can’t We do Better in Terms of Cancer Treatment?
39% Drop
17% Drop
34% Drop
53% Drop

30. Drug Resistance

32. Emergence of Drug Resistance
View Drug-Efflux Movie
Figure The Biology of Cancer (© Garland Science 2007)

35. Non-P-Glycoprotein Cancer Drug Resistance Mechanisms
Table The Biology of Cancer (© Garland Science 2007)

36. Molecular Mechanisms of Resistance to Chemotherapy
Pitot, Figure 20-10

37. Tolerated Doses,
Effective Doses, and
Side Reactions

38. Therapeutic Index: 95% Tolerated Dose vs 50% Effective Dose

40. Why Is Cancer Such a Wide-spread and Intractable Problem?
See Vogelstein, 2013
Cancer Genome Landscape.

41. Two Turning Point Questions

42. The picture below is showing an important mechanism involving cancer drug resistance. What is the coiled structure that is shown below?
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43. We showed a long list of Limitations in Cancer Chemotherapy: Side Reactions or Host Effects that Limit the Value of Cancer Chemotherapy. Give any one of those limiting factors.
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End Presentation for Tuesday May 3, 2016

44. Breast cancer incidence looks like it is going up after 1980
Breast cancer incidence looks like it is going up after Give one example of something that could give or cause this result.
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End Last Presentation Here: May 2, 2017

45. What is this graph telling us about age-adjusted Breast Cancer Mortality in the US between 1930 and 1990?
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46. Cell Cycle Specific Agents in Cancer Chemotherapy