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Natural

Acquired

Categories of resistance

Kinetic

Biochemical

Pharmacologic

Kinetics and resistance

Relates to cycle and phase specificity

Overcome by reducing tumor bulk

Use of combinations to include drugs affecting resting cells

Schedule drugs to prevent phase escape

Biochemical resistance

Inability to convert drug to active form

Decrease drug uptake

Increased efflux

Changes in intracellular target

Increased inactivation

Increased rate of repair of damage DNA

bcl-2 overexpression (blocks apoptosis)

p53 mutations

MDR-drug efflux

Use of agents to rescue normal cells so allowing use of higher doses of chemotherapy

Pharmacologic resistance

Poor or erratic absorption

Increased excretion

Increased catabolism

Drug interactions

Poor transport of agents into some tissues (entry of drugs into CNS)

Future

Understand molecular basis of cancer

Understand differences between normal and malignant cells

Current chemotherapy regimens may be a crude beginning

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