Cancer Chemotherapy - PowerPoint PPT Presentation

1 / 32
About This Presentation
Title:

Cancer Chemotherapy

Description:

2nd leading COD to Heart Disease. Men Prostate, lung, colo-rectal. Women Breast, lung, colo-rectal ... 60 human tumor cell lines based on diverse histology ... – PowerPoint PPT presentation

Number of Views:344
Avg rating:3.0/5.0
Slides: 33
Provided by: uwacadw
Category:

less

Transcript and Presenter's Notes

Title: Cancer Chemotherapy


1
Cancer Chemotherapy
  • Review Ch. 52
  • Goodman Gilman

2
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

3
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

4
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)

5
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
6
Risk Factors
  • Age
  • Sex
  • Ethnicity
  • Environment
  • Lifestyle
  • Infections
  • Genetics
  • Medications

7
Treatment Options
  • Surgery solid tumors
  • Radiation solid tumors
  • Chemotherapy
  • Hormonal Therapy
  • Biological Response Modifiers
  • Gene Therapy
  • BMT
  • Supportive Therapy (Other drugs)

8
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?

9
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

10
The Cell Cycle (flashback)
11
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

12
Obstacles to Chemotherapy
13
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

14
Toxicity Roadmap - handout
15
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)

16
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

17
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

18
ObstaclesDetection vs. Prognosis
19
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

20
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

21
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

22
Resistance cont
23
Multidrug Resistance
  • Due to Increased expression of pumps
  • Affected Drugs
  • Antibiotics
  • Vinca alkaloids
  • Surprising cross-resistance!
  • No common mechanism of action!

24
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

25
Chemo Strategies cont
  • Intermittent Chemotherapy

26
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

27
Combination Chemotherapy
28
Cytotoxic Drugs
  • Classes
  • Alkylating agents
  • Antimetabolites
  • Antitumor antibiotics
  • Mitotic inhibitors
  • Topoisomerase inhibitors
  • Other

29
Cytotoxic Drugs cont
  • Disrupt DNA synthesis
  • Block mitosis
  • Disrupt protein synthesis
  • Target cell replication
  • High Growth Fraction most affected
  • Cell cycle specific vs. nonspecific

30
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)

31
The Cell Cycle (flashback)
32
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
Write a Comment
User Comments (0)
About PowerShow.com