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📚 ANTICANCER DRUGS — Exam Notes (Ch. 35)

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I. OVERVIEW

• >25% of the US population will face a cancer diagnosis
• <25% cured by surgery/radiation alone → most need systemic chemotherapy
• Only ~10% achieve cure or prolonged remission with chemo
• Overall 5-year survival rate ≈ 68%
• Cancer = #2 cause of mortality (after cardiovascular disease)

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II. PRINCIPLES OF CANCER CHEMOTHERAPY

Goal

• Cause lethal cytotoxic event or apoptosis in cancer cells
• Attack DNA or metabolic sites (purines/pyrimidines) essential for cell replication

Key Problem

• Most chemo drugs do NOT distinguish neoplastic from normal proliferating cells
• → Steep dose-response curve for both therapeutic AND toxic effects
• Newer agents: block immune checkpoints → let body attack cancer (but cause autoimmune toxicity)

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A. Treatment Strategies

1. Goals of Treatment

2. Indications for Treatment

• Adjuvant chemo - after surgery/radiation to attack micrometastases
• Neoadjuvant chemo - before surgery to shrink tumor
• Maintenance chemo - low doses to prolong remission

3. Tumor Susceptibility & Growth Cycle

• Rapidly dividing cells → MORE sensitive to chemo
• Slowly proliferating / G₀ phase cells → LESS sensitive (often survive)

Cell Cycle Specificity

Tumor Growth Rate

• Solid tumors: rapid growth initially, then slows as tumor enlarges (poor vascularization/oxygen)
• Reducing tumor burden → pushes remaining cells into active division → more susceptible to chemo

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B. Treatment Regimens & Scheduling

1. Log Kill Phenomenon ⚠️

• Chemo destroys a constant FRACTION of cells (first-order kinetics), not a fixed number
• Example: 5-log kill = 99.999% reduction → 10⁵ cells killed per treatment
• Leukemia diagnosed at ~10⁷ cells → after 5-log kill → 10² cells remain (patient asymptomatic but NOT cured)
• Unlike bacteria (immune system clears rest), tumor cells need additional treatment

2. Pharmacologic Sanctuaries

• CNS is a sanctuary site - transport barriers block many drugs
• May require intrathecal drug delivery or craniospinal irradiation

3. Treatment Protocols

• Combination chemo > single-drug in most cancers

Combination Chemo Advantages:

1. Maximal cell killing within tolerated toxicity
2. Broader range of cell lines covered
3. Delays/prevents drug resistance

How to Combine:

• Use drugs with different mechanisms and different toxicity profiles
• Drugs with same dose-limiting toxicity (e.g., myelosuppression) → must reduce doses

Example: R-CHOP (Non-Hodgkin Lymphoma) = Rituximab + Cyclophosphamide + Hydroxydaunorubicin (doxorubicin) + Oncovin (vincristine) + Prednisone

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C. Resistance & Toxicity

1. Resistance

• Some cells inherently resistant (e.g., melanoma)
• Others acquire resistance by mutation, especially with prolonged suboptimal dosing
• Prevention: short-term, intensive, intermittent combination therapy

2. Multidrug Resistance (MDR)

• Caused by P-glycoprotein (transmembrane "permeability" glycoprotein)
• Uses ATP-dependent pump to expel drugs from cells
• Cross-resistance among: Vinca alkaloids, dactinomycin, anthracycline antibiotics, colchicine
• All are naturally occurring, hydrophobic with positive charge at neutral pH
• Verapamil can inhibit the pump (but has its own pharmacologic side effects)

3. Toxicity

• Buccal mucosa
• Bone marrow (myelosuppression → infection risk)
• GI mucosa
• Hair follicles (alopecia)

Common Adverse Effects:

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DRUG CLASSES — Quick Reference

Antimetabolites

Antibiotics

Alkylating Agents

Microtubule Inhibitors

Steroid Hormones & Antagonists

Monoclonal Antibodies (-mab)

Tyrosine Kinase Inhibitors (-nib)

Others

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MECHANISMS AT A GLANCE (Fig. 35.2)

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KEY MNEMONICS & HIGH-YIELD FACTS

• "Log kill" = constant fraction killed per dose (NOT constant number)
• P-glycoprotein = multidrug resistance pump (ATP-dependent efflux)
• G₀ phase cells = resistant to most chemo (not dividing)
• Cell cycle-specific = best for leukemias (high growth fraction)
• Cell cycle-nonspecific = works on solid tumors too
• Combination chemo = different mechanisms + different toxicities = better outcomes
• Tumor burden at diagnosis ≈ 10⁹ cells (1g mass, like a small grape)
• CNS = pharmacologic sanctuary site