26 Principles of Pharmacology - Clinical Cancer Chemotherapy and Drug Resistance
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Course
Pharmacology
Institution
Pharmacology
The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Donald Kufe
1 HST-151
Principles of Clinical Cancer Chemotherapy and Drug Resistance
Cancer Mortality: 2000 = 553,091; Est.2003 = 556,500
Cancer Chemotherapy -- Effectiveness by Disease
1. Curative
• Acute Lymphocytic Leukemia, Hodgkin’s Disease, Diffuse Histiocytic
Lymphoma, Burkitt’s Lymphoma
• Testicular Cancer, Choriocarcinoma
• Wilms’ Tumor,* Ewing’s Sarcoma,* Embryonal Rhabdomyosarcoma*
2. Probably Curative
• Acute Myelogenous Leukemia
• Small Cell Lung Cancer, Breast Cancer,* Osteogenic Sarcoma*
3. Major Therapeutic Benefit (Short of Cure)
• Head and Neck Cancer, Cervical Cancer, Metastatic Breast Cancer, Ovarian
Cancer
• Soft Tissue Sarcoma
• Nodular Lymphomas, Chronic Leukemias
• Insulinomas
4. Limited Effectiveness
• Lung Cancer
• GI Cancer
• Prostate Cancer
• Melanoma
* Adjuvant chemotherapy: Drugs administered after removal of all detectable disease.
, 2 HST-151
Acute Lymphocytic Leukemia: Induction of Chemotherapy
1. First Order Kinetics
2. Host Toxicity
3. Selectivity
4. Combination Chemotherapy
1. First Order Kinetics
A given dose/unit time of chemotherapy will kill a constant percentage of cells, not a
constant number. This means that the same dose which decreases the tumor burden from
106 to 103 cells will be needed to decrease the burden from 103 to 100 cells.
First Order Kinetics
100 10 6
Percent Surviving Cells
10 10 5
Cell Number
1 10 4
0.1 10 3
0.01 10 2
0.001 10 1
0.0001 10 0
Drug Dose / Unit Time
Assuming an initial tumor burden of 106 cells, a treatment which is 99.9% effective will
still leave 103 cells untouched. Thus, treatment may eliminate clinical symptoms, but the
tumor can recur. Treatment should aim for 10-1 cells or less remaining to ensure a high
percentage of cures.
“Log-kill hypothesis”
, 3 HST-151
• Dashed line = no treatment.
• Top solid line = moderate, infrequent dosing of chemotherapy which prolongs
survival but results in recurrent symptoms and eventual death.
• Middle line = aggressive treatment. Cell kill exceeds regrowth and treatment is
sufficiently long to sterilize tumor (patient is cured).
• Bottom line = primary tumor is surgically removed or debulked, and adjuvant
chemotherapy is used to kill remaining occult tumor.
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