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

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.

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?

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?

Cancer Chemotherapy: How Are We Doing? Lung Cancer 5 Year Survival 1970 7% Lung Cancer 5 Year Survival 2000 14% The Effect of Earlier Diagnosis. How Much Real Progress is There? Show Presentation Folder Title: Under Cancer War: Cancer Research the 90Billion Metaphor

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

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

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

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

Declining Death Rates No real improvement of treatment effectiveness

Two Turning Point Questions

What is this graph telling us about prevention and/or treatment of these cancers from 1950 to 1990? Response Counter

What was done to produce the reduction in breast cancer dimensions between these two magnetic resonance images? Response Counter

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

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

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

(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 12-40 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?

Figure 12-40 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)

Cell Cycle-directed Cancer Chemotherapy

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)

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

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

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

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

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

Drug Resistance

Emergence of Drug Resistance View Drug-Efflux Movie Figure 16.23 The Biology of Cancer (© Garland Science 2007)

Non-P-Glycoprotein Cancer Drug Resistance Mechanisms Table 16.2 The Biology of Cancer (© Garland Science 2007)

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

Tolerated Doses, Effective Doses, and Side Reactions

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

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

Two Turning Point Questions

The picture below is showing an important mechanism involving cancer drug resistance. What is the coiled structure that is shown below? Response Counter

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. Response Counter End Presentation for Tuesday May 3, 2016

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

What is this graph telling us about age-adjusted Breast Cancer Mortality in the US between 1930 and 1990? Response Counter

Cell Cycle Specific Agents in Cancer Chemotherapy