Title: Cancer Chemotherapy
1Cancer Chemotherapy
- Review Ch. 52
- Goodman Gilman
2Why 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
3National 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
4What 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)
5Common 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
6Risk Factors
- Age
- Sex
- Ethnicity
- Environment
- Lifestyle
- Infections
- Genetics
- Medications
7Treatment Options
- Surgery solid tumors
- Radiation solid tumors
- Chemotherapy
- Hormonal Therapy
- Biological Response Modifiers
- Gene Therapy
- BMT
- Supportive Therapy (Other drugs)
8Modalities 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?
9How 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
10The Cell Cycle (flashback)
11Drug Targets
- Chemotherapy drugs are more toxic to tissue with
high growth fraction - High fraction rapidly growing
- Disseminated cancers
- Low fraction slow growing
- Solid tumors
12Obstacles to Chemotherapy
13Obstacles 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
14Toxicity Roadmap - handout
15Major 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)
16Major 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
17Obstacles 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
18ObstaclesDetection vs. Prognosis
19Absence 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
20Resistance 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
21Anticancer 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
-
22Resistance cont
23Multidrug Resistance
- Due to Increased expression of pumps
- Affected Drugs
- Antibiotics
- Vinca alkaloids
- Surprising cross-resistance!
- No common mechanism of action!
24Chemo 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
25Chemo Strategies cont
- Intermittent Chemotherapy
26Chemo 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
27Combination Chemotherapy
28Cytotoxic Drugs
- Classes
- Alkylating agents
- Antimetabolites
- Antitumor antibiotics
- Mitotic inhibitors
- Topoisomerase inhibitors
- Other
29Cytotoxic Drugs cont
- Disrupt DNA synthesis
- Block mitosis
- Disrupt protein synthesis
- Target cell replication
- High Growth Fraction most affected
- Cell cycle specific vs. nonspecific
30Cell 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)
31The Cell Cycle (flashback)
32Cell 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