Cancer Chemotherapy

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Cancer Chemotherapy

• Review Ch. 52
• Goodman Gilman

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Why should I care?

• 2nd leading COD to Heart Disease
• Men Prostate, lung, colo-rectal
• Women Breast, lung, colo-rectal
• gt 500,000 deaths in the U.S. annually
• 50 of Patients are curable
• At least 10 types of curable cancer
• 33 cured with radiation or surgery
• 17 receive chemotherapy
• Provides palliative care
• Rapidly developing field

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National Cancer Institute (NCI)

• 20,000 new drug candidates screened per year
• Primary screen
• 60 human tumor cell lines based on diverse
  histology
• leukemia, melanoma, lung, colon, kidney, ovary,
  brain
• Secondary screen
• immunodeficient mice (human cells, no rejection)
• Alternative screen
• HTCFA (human-tumor-colony forming assay)
• individual tumor types and occasionally
  individual patients
• Phase I trials
• Clinical pharmacology - determination of dose
  toxicity
• Phase II trials
• Agent tested against various tumor types (tumor
  panels)
• Phase III trials
• broad multi-center testing
• includes randomization some patients receiving
  new drug, others receiving the standard treatment
• lots of statistical analysis to verify
  statistical significance of treatment
• Phase IV trials
• Find toxicities not discovered in Phase III

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What is Cancer?

• Disease of Cells
• Lack control mechanisms (feedback)
• Chromosomal abnormalities
• bcl-2 oncogene (apoptosis suppressor)
• p53 gene (tumor suppressor turned oncogene)
• Tumor stem cells (small population)
• Cellular Immortality (telomerase)
• Metastases (travel to distant sites)
• Clonogenic (colony forming ability)

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Common Cancer lingo

• Carcinoma epithelial origin
• Sarcoma connective or muscle origin
• Lymphoma Lymphatic tissue
• Hodgkins distinctive cell type
• Leukemia hematopoetic origin
• Acute/Chronic
• Myelogenous abnormal appearing WBC
• Lymphocytic High lymphoblast (young WBC)
• Myeloma muscle tissue
• Neuroblastoma solid tumor adrenal gland
• Melanoma skin pigment cells

MAIN
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Risk Factors

• Age
• Sex
• Ethnicity
• Environment
• Lifestyle
• Infections
• Genetics
• Medications

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Treatment Options

• Surgery solid tumors
• Radiation solid tumors
• Chemotherapy
• Hormonal Therapy
• Biological Response Modifiers
• Gene Therapy
• BMT
• Supportive Therapy (Other drugs)

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Modalities of Chemotherapy

• Curative
• Childhood leukemia, osteogenic sarcoma, lymphoma,
  testicular, Wilm tumor Ewings sarcoma
• Palliative
• Improve survival neuroblastoma, adult leukemia,
  myeloma, lymphoma, breast, stomach, ovarian,
  endometrial, uterine cancers
• Palliate symptoms CLL, CML, prostatic, colon,
  head neck, aggressive lymphomas
• Adjuvent follow surgery/radiation
• Breast, ovarian, colon
• Neoadjuvent prior to surgery
• Osteosarcoma, rectal, head neck
• Prevention
• Tamoxifen, ASA, folic acid, sunscreen, lead
  suits?

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How to Target Cancer Cells?

• Exploit properties unique to Cancer cells
• The Growth Factor (Fraction)
• Major determinant of chemotherapy effectiveness
• Defined ProliferatingResting cell ratio
• Related to the Cell Cycle
• Enzyme production
• Vascularization

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The Cell Cycle (flashback)
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Drug Targets

• Chemotherapy drugs are more toxic to tissue with
  high growth fraction
• High fraction rapidly growing
• Disseminated cancers
• Low fraction slow growing
• Solid tumors

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Obstacles to Chemotherapy
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Obstacles to Chemotherapy

• Healthy High Growth Fraction Areas
• Bone marrow
• Skin
• Hair follicles
• Sperm
• Gastrointestinal tract
• Toxicity is Dose Limiting
• Poor selectivity of drugs
• Healthy and cancerous cells affected

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Toxicity Roadmap - handout
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Major Toxicities

• Bone Marrow Suppression
• Neutropenia Low WBC
• G-CSF (filgrastim) GM-CSF (sargramostim)
• Thrombocytopenia Low platelete count
• Oprelvekin (Neumega)
• Anemia Low RBC
• http//www.medscape.com/mp/rc/anemia
• Erythropoetin
• Digestive Tract Problems
• Stomatitis inflammation of oral mucosa
• Diarrhea impaired nutrient absorption
• Nausea Vomiting (N/V)
• Occurs 17 98 (Psych factors)
• Ondansetron (Zofran) and others (handout)

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Major Toxicities cont

• Other
• Alopecia hair loss
• Reproductive sterility in males
• Hyperuricemia increased urination (DNA)
• Extravasation of vesicants
• Drug-specific (hepatic, coronary, etc)
• Carcinogenesis some patients sensitive

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Obstacles cont

• Cure requires 100 cancer cell death
• Nearly impossible!
• Kinetic problems (drugs are 1st order)
• Nonparticipation of immune system
• Treatment duration?
• Example
• Patient has 1012 cancer cells systemically
• Treatment kills 99.999
• Patient still has 107 cancer cells

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ObstaclesDetection vs. Prognosis
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Absence of Early Detection

• Only cervical cancer is detectable early
• Consequences of late detection
• Metastases
• Decreased responsiveness to Chemo
• Solid tumors respond poorly
• Drug resistance
• Tumor Cell Heterogeneity
• Limited Access (diffusion, transport, etc.)
• Patient debilitation

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Resistance Mechanisms

• Often produced by the drug itself (mutagen)
• Cellular adaptation ? altered enzyme levels
• Example Methotrexate increased dihydrofolate
  reductase produced to overwhelm drug
• Reduced drug transport into cells
• Reduced molecular target affinity
• Stimulation of alternative biosynthetic pathways
• Impaired activation or increased metabolism
• Cellular repair mechanisms for DNA
• Example repair of crosslinks or scission caused
  by alkylating agents
• Multiple Drug Resistance P-glycoprotein
• Drug efflux pumps become overexpressed

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Anticancer Drug Resistance

• Primary
• Absence of a first response
• Non-small cell lung colon cancers
• Acquired
• Increased expression of MDR1
• Creates more surface glycoprotein
• Uses ATP to expel a variety of molecules

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Resistance cont
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Multidrug Resistance

• Due to Increased expression of pumps
• Affected Drugs
• Antibiotics
• Vinca alkaloids
• Surprising cross-resistance!
• No common mechanism of action!

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Chemo Strategies

• Intermittent chemotherapy
• Combination chemotherapy
• Regional drug delivery
• Intra-arterial solid tumors
• Intrathecal CNS delivery (non-BBB drugs)
• Intracavity pleural, peritoneal, bladder
• Portal Vein Liver
• Brain Implants

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Chemo Strategies cont

• Intermittent Chemotherapy

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Chemo Strategies cont
Combination Chemotherapy

• Suppression of Drug Resistance
• Increased Cancer kill rates
• Reduced systemic toxicity
• Selection Criteria
• Each drug effective alone
• Different mechanism of action
• Minimal overlapping toxicities

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Combination Chemotherapy
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Cytotoxic Drugs

• Classes
• Alkylating agents
• Antimetabolites
• Antitumor antibiotics
• Mitotic inhibitors
• Topoisomerase inhibitors
• Other

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Cytotoxic Drugs cont

• Disrupt DNA synthesis
• Block mitosis
• Disrupt protein synthesis
• Target cell replication
• High Growth Fraction most affected
• Cell cycle specific vs. nonspecific

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Cell Cycle Specific Drugs

• Toxic to cells in a specific phase
• Vincristine - causes mitotic arrest
• Only effective in M-Phase
• Require long presence
• Prolonged infusions
• Multiple doses
• Known as Schedule Dependent Drugs
• Classes
• Antimetabolites (S)
• Mitotic Inhibitors (M)
• Asparaginase (G1 S)
• Bleomycin (G2)
• Etoposide (G2)

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The Cell Cycle (flashback)
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Cell Cycle Nonspecific Drugs

• Act during any phase (even G0)
• Synergistic w/cell cycle specific drugs
• More toxic to proliferating cells
• Cells use G0 for repair
• Toxicity apparent during proliferation
• Include
• Alkylating Agents
• Most antitumor antibiotics