Download Cancer Chemotherapy

Cancer
Chemotherapy
Prof. Rafi Korenstein
Dept. of Physiology and Pharmacology
Faculty of Medicine, Tel-Aviv University
Bibliography
• * Pharmacology (Rang, Dale & Ritter)
• Basic & Clinical Pharmacology
(Katzung)
• Cancer – Principles & Practice of
Oncology (DeVita, Hellman & Rosenberg)
ONCOLOGY
Epidemiology
Leading causes of death
Percentage of Total Deaths, US
Heart Diseases
31.4
23.3
Cancer
Cerebrovascular Diseases
6.9
4.7
Chronic Obstructive Lung Diseases
Accidents
4.1
Pneumonia & Influenza
3.7
Diabetes Mellitus
Suicide
2.7
1.3
Homicide
0.9
HIV Infection
0.7
Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000:50;22.
Cancer Biology
Cancer cells vs normal cells
CANCER CELLS
NORMAL CELLS
Frequent
mitoses
Normal
cell
Nucleus
Blood vessel
Few
mitoses
Abnormal
heterogeneous cells
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Neovascularization
Oncogene expression is rare
Intermittent or coordinated
growth factor secretion
Presence of tumor suppressor
genes
Emergence of tumor cell heterogeneity
Primary Neoplasm
TRANSFORMATION
TUMOR EVOLUTION
AND PROGRESSION
Metastases
METASTASIS
Genetic and epigenetic instability
TUMOR EVOLUTION
AND PROGRESSION
Tumorigenesis
Normal
cell
Initial
genetic change
Secondary
genetic change
(eg, loss of function of pRb
or overexpression of c-myc)
(eg, dysfunction of p53
or overexpression of bcl-2)
Increase in
cell proliferation
and apoptosic
cell death
Decrease
in apoptosic
cell death
Subsequent
genetic change
Further alterations
in phenotype
(eg, invasiveness
and metastasis)
Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134.
Typical doubling times
• 24 hours for some lymphoma
• 2 weeks with some leukemias
• 3 months with mammary cancer
The doubling process
Malignant
transformation
Exponential growth
Dividing
Normal
cell
4 cells
Doubling
Doubling
2 cancer
cells
8 cells
1 million cells
(20 doublings)
undetectable
Doubling
16 cells
1 trillion cells
(40 doublings – 2 lb/1kg)
1 billion cells
(30 doublings)
lump appears
41 – 43
doublings
— Death
Tumor growth and detection
Number of
cancer cells
1012
Diagnostic
threshold
(1cm)
109
time
Undetectable
cancer
Detectable
cancer
Limit of
clinical
detection
Host
death
Methods of Cancer
Treatments
-Surgery
-Radiotherapy
-Chemotherapy
-Immunotherapy
-Biological Therapy
Chemotherapuetic Agents
Effects of chemotherapy
• Selective toxicity based on characteristics that
distinguish malignant cells from normal cells
• Antineoplastic effects
– Cell death
– Cell growth inhibited
– Cell differentiation
Haskell CM. Cancer Treatment. 4th ed. 1995;32.
Drugs used in cancer chemotherapy
Cytotoxic druges
- Alkylating agents and related
drugs
- Antimetabolites
- Antitumor antibiotics
- Antimicrotubule agents
- Miscellaneous agents
Hormones
Others
characteristics of cytotoxic drugs
• Mostly antiproliferative
• Action during the S phase of the cell cycle
• No specific inhibitory effect on invasiveness, loss of
differentiation
Side toxic effects
• Cytotoxic drugs act on dividing cells (both cancer and
normal cells)
• They will affect all rapidly dividing normal tissues
general toxic effects
• Bone marrow: decreased leukocyte production
leading to decreased resistance to infection
• Blood: may affect erythropoesis leading to anemia
and decreased coagulation.
• Loss of hair
• Damage to gastrointestinal epithelium
toxic effects of prolong use
• Deprssion of gametogenesis leading to sterility
• Increased risk of acute non-lymphocytic
leukemia and other malignancies
Administration of cytotoxic chemotherapy
• Dose that will kill 99.99% of cells, if used to treat
a tumor with 1011 cells will leave 107 viable cells.
• Due to the toxic side effects the dose is
restricted.
• Schedules of chemotherapy are necessary to
produce as near total cell kill as possible.
• In contrast to situation with microorganisms, very
little reliance can be placed on host`s
immunological response against remaining
tumor.
DNA AND ITS ASSOCIATED PROCESSES AS TARGETS FOR
CANCER THERAPY
Classes of DNA-interactive agents and their molecular interactions with DNA
Cytotoxic agents
Alkylating agents: Mechanism of action
• Polyfunctional compounds which alkylate
efficiently either directly or after being
metabolized
• Cytotoxicity results from alkylation
of guanine and interference with DNA
replication/transcription to RNA
• Cell-cycle–phase nonspecific (although dividing
cells are more prone to their action)
Gerson SL. Current Cancer Therapeutics. 3rd ed. 1998;1.
Monoalkylation and crosslinking chemistry of alkylating agents
Cross-linking interferes both with transcription and replication