Download CxChemoPart1(NoTP)

Cancer Chemotherapy
Part I: General Cancer Chemotherapy
Chapter 16; Pages 797 to 815A
also Section 16.11: Drug Resistance
Folder Title: CxChemoPart1(NoTP)
Updated: May 3, 2016
Turning Point Opening Slide
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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:
Chemothe_1940to1990
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
Turning Point Opening Slide
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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
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Thursday, April 28, 2016: Ended with Two Turning Point Questions:
Slides 14 & 15
Did Slides 17 to 22 on Alkylating Agents and Antimetabolites
Tuesday May 3, 2016: Review Slides 17 to 22
Slide 23: Selectivity and Specificity in Cancer Chemotherapy
Slides 24 to 26: Cell Cycle Specific Anticancer Agents
Combination Chemotherapy: Slide 27
Slides 28 and 29: Numbers of Chemotherapy Agents:
Why Can’t We do better in terms of cancer treatment?
Drug Resistance: Slides 30 to 36
BRCA2 DNA-Repair Based Chemotherapy Slides 40 and 41
Slides 37 – 39 Tolerated Doses, Effective Doses, Side-Reactions, Therapeutic Index
Turning Point Questions: 42, 43, 44
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?
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
Taxol
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
Cell Cycle Specific Agents in Cancer Chemotherapy
What if we combine Anti-cancer Drugs Working by Different Mechanisms?
Physician’s Desk Reference
Oncology Reference Guide
203 Oncology Treatment Agents
Published in 2003
We Have Over 200 Agents Now
Why Can’t We do Better in Terms of Cancer Treatment?
Drug Resistance
Emergence of Drug Resistance
Figure 16.23 The Biology of Cancer (© Garland Science 2007)
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
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)
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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.
Two Turning Point Questions
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End Presentation for Tuesday May 3, 2016
What is this graph telling us about age-adjusted Breast
Cancer Mortality in the US between 1930 and 1990?
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Breast cancer incidence looks like it is going up after 1980.
Give one example of something that could give or cause
this result.
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