Therapeutics 2 — Cancer Chemotherapy Synopsis

---

PART 1: BASIC PRINCIPLES OF CANCER CHEMOTHERAPY

1.1 The Nature of Cancer

• Expression of abnormal cell-surface antigens (often fetal-type)
• Chromosomal abnormalities: translocations, fusions, gene amplifications
• Tumor stem cells: clonogenic cells capable of metastasis
• Genetic instability → progressive selection of drug-resistant subclones
• Resistance may develop to radiotherapy, cytotoxic chemo, targeted therapy, and immunotherapy

— Katzung's Basic and Clinical Pharmacology, 16th Edition, p. 1475

---

1.2 Cell Cycle & Drug Classification

A. Cell Cycle–Specific (CCS) Agents

B. Cell Cycle–Nonspecific (CCNS) Agents

---

1.3 Log-Kill Hypothesis & Tumor Burden

• Chemotherapy kills a fixed proportion (log fraction) of tumor cells per cycle, not a fixed number
• A drug that kills 99.9% (3-log kill) leaves 10⁵ cells alive in a 10⁸-cell tumor
• Implication: Multiple cycles are required to reduce tumor burden to zero or to levels controllable by the immune system
• Gompertzian growth: Tumors grow rapidly when small; growth slows as size increases. Small tumors respond better to chemo (higher growth fraction)

---

1.4 Principles of Combination Chemotherapy (Rationale)

1. Each drug should have activity as a single agent against the tumor
2. Non-overlapping toxicities — allows full dosing of each agent
3. Different mechanisms of action — additive/synergistic kill
4. Different resistance mechanisms — minimizes cross-resistance
5. Optimal scheduling — cell cycle–specific agents given after CCNS debulking

---

1.5 Drug Resistance

• Primary (intrinsic): Pre-existing resistant clones selected during treatment
• Acquired: Develops during therapy via mutations or epigenetic change

---

1.6 Goals of Therapy

• Adjuvant chemotherapy: After surgery/radiation, to eliminate micrometastases
• Neoadjuvant chemotherapy: Before surgery, to shrink tumor (improve resectability)
• Induction chemotherapy: Intensive initial therapy to achieve remission

---

1.7 General Principles of Toxicity

---

---

PART 2: CLASSIFICATION OF CANCER CHEMOTHERAPEUTIC AGENTS

---

CLASS 1: ALKYLATING AGENTS

• Interstrand and intrastrand DNA cross-links
• Inhibition of DNA replication and transcription
• Cell cycle–nonspecific (though maximal effect in late G₁ and S phase)

---

1a. Nitrogen Mustards

1b. Nitrosoureas

1c. Platinum Analogs (Platinum Coordination Complexes)

1d. Other Alkylating Agents

---

CLASS 2: ANTIMETABOLITES

---

2a. Folate Antagonists

2b. Pyrimidine Analogs

2c. Purine Analogs

---

CLASS 3: NATURAL PRODUCTS

3a. Vinca Alkaloids (M phase — CCS)

3b. Taxanes (M phase — CCS)

3c. Topoisomerase Inhibitors

Topoisomerase II Inhibitors (Epipodophyllotoxins)

Topoisomerase I Inhibitors (Camptothecins)

3d. Antitumor Antibiotics

---

CLASS 4: TARGETED THERAPY

4a. Tyrosine Kinase Inhibitors (TKIs)

BCR-ABL Inhibitors (for CML / Ph+ ALL)

EGFR Inhibitors (NSCLC, colorectal)

Other Notable TKIs

4b. Monoclonal Antibodies

4c. Antibody-Drug Conjugates (ADCs)

---

CLASS 5: HORMONAL AGENTS

---

CLASS 6: MISCELLANEOUS AGENTS

---

QUICK REFERENCE: COMMON ADR ASSOCIATIONS

---

SUMMARY CLASSIFICATION TABLE

---

Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 54 (pp. 1475–1524); Goodman & Gilman's The Pharmacological Basis of TherapeuticsThis synopsis covers both topics comprehensively. Here's a quick orientation to what's included:

---

• Nature of cancer and tumor biology
• Cell cycle phases and CCS vs. CCNS drug classification
• Log-kill hypothesis and Gompertzian tumor growth
• Rationale for combination chemotherapy (with classic regimen examples)
• Mechanisms of drug resistance (including P-glycoprotein, target mutations)
• Goals of therapy: curative, control, palliative; adjuvant vs. neoadjuvant vs. induction
• General toxicity profile (bone marrow, GI, gonads, secondary malignancies)

1. Alkylating agents — nitrogen mustards, nitrosoureas, platinum analogs
2. Antimetabolites — folate antagonists, pyrimidine analogs, purine analogs
3. Natural products — vinca alkaloids, taxanes, topoisomerase I & II inhibitors, antitumor antibiotics
4. Targeted therapy — BCR-ABL TKIs (all generations), EGFR inhibitors, checkpoint inhibitors (PD-1/CTLA-4), ADCs
5. Hormonal agents — SERMs, AIs, GnRH agonists, androgen-axis blockade
6. Miscellaneous — proteasome inhibitors, PARP inhibitors, mTOR inhibitors, IMiDs

---

Gout — Comprehensive Synopsis

---

1. DEFINITION

— Robbins & Kumar Basic Pathology, p. 4380; Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 1028

---

2. EPIDEMIOLOGY

• Most common in men (95% of cases); women typically affected postmenopause
• Men typically develop gout in their 4th–6th decades
• Asymptomatic hyperuricemia is common (~19% of the US population), but only 1 in 8 patients with urate levels of 7–8 mg/dL develop clinical gout over 14 years
• Risk rises significantly with urate >9 mg/dL or in the presence of comorbidities (CKD, cardiovascular disease, obesity, diabetes)

---

3. PATHOPHYSIOLOGY

3.1 Uric Acid Metabolism

3.2 Causes of Hyperuricemia

3.3 Crystal-Induced Inflammation

1. Synoviocytes phagocytose urate crystals → release prostaglandins, IL-1, LTB₂
2. Neutrophils recruited into joint space → amplify inflammation (release free radicals, lysosomal enzymes)
3. Macrophages appear later → ingest crystals → release further cytokines
4. IL-1β is the central mediator: NLRP3 activates caspase-1 → cleaves pro-IL-1β to active IL-1β
5. Crystal-induced lysosomal membrane damage → enzyme leakage → tissue injury

— Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 1028

---

4. CLINICAL STAGES

---

5. DIAGNOSIS

5.1 Synovial Fluid Analysis (Gold Standard)

• Needle-shaped MSU crystals that are negatively birefringent under polarized light (yellow when parallel to slow ray of compensator)
• Intracellular crystals in neutrophils during acute attack

5.2 Serum Uric Acid

• Hyperuricemia (>6.8 mg/dL) is necessary but not sufficient
• May be normal during acute attack (crystals precipitate as uric acid drops)

5.3 Imaging

— Grainger & Allison's Diagnostic Radiology, p. 1125

---

6. TREATMENT

6.1 Treatment Goals

1. Relieve acute gouty attacks rapidly
2. Prevent recurrent attacks with prophylactic therapy
3. Prevent complications — tophi, nephrolithiasis, nephropathy, joint damage
4. Lower serum uric acid to target <6 mg/dL (symptomatic patients)

• ≥2 gouty attacks/year
• Presence of tophi
• Chronic kidney disease
• Uric acid nephrolithiasis

---

6.2 TREATMENT OF ACUTE GOUT

A. NSAIDs

• Indomethacin is the classic choice (50 mg TID × 5–7 days), though all NSAIDs are likely effective
• MOA: Inhibit COX-1/COX-2 → ↓ prostaglandin synthesis → reduce inflammation
• Avoid in: Peptic ulcer, renal impairment, anticoagulation, heart failure
• Start within 24–48 hours of onset for best effect

B. Colchicine

• Plant alkaloid from Colchicum autumnale
• MOA: Binds tubulin → depolymerizes microtubules → impairs neutrophil motility and migration into the inflamed joint; also blocks mitotic spindle (cell division)
• Must be given within 36 hours of attack onset to be effective
• Relieves pain typically within 12 hours
• Dose: Low-dose colchicine (1.2 mg then 0.6 mg one hour later) is as effective as high-dose with fewer GI side effects
• ADRs:
  • Acute: Nausea, vomiting, abdominal pain, diarrhea (most common; dose-dependent)
  • Chronic: Myopathy, neutropenia, aplastic anemia, alopecia
  • Avoid in: Pregnancy; caution with hepatic/renal/cardiovascular disease
  • Drug interactions: Metabolized by CYP3A4 and is a P-gp substrate → increased toxicity with CYP3A4 inhibitors (clarithromycin, itraconazole) and P-gp inhibitors (amiodarone, verapamil)

C. Corticosteroids

• Used when NSAIDs and colchicine are contraindicated (e.g., renal impairment)
• Intra-articular corticosteroids when 1–2 joints involved
• Systemic (oral prednisone, IV methylprednisolone) for polyarticular or severe gout
• ADR: Rebound flare on tapering → taper slowly over 2–3 weeks

---

6.3 URATE-LOWERING THERAPY (CHRONIC GOUT MANAGEMENT)

Important note: Initiating urate-lowering therapy can precipitate an acute attack due to rapid changes in serum urate. Always co-prescribe prophylactic low-dose colchicine or NSAID for ≥6 months when starting these agents.

A. Xanthine Oxidase Inhibitors (First-line)

1. Allopurinol

2. Febuxostat

---

B. Uricosuric Agents

---

C. Recombinant Uricase (Pegloticase)

---

6.4 IL-1 INHIBITORS (Emerging/Refractory Cases)

• Anakinra (IL-1Ra), Canakinumab (anti-IL-1β monoclonal Ab), Rilonacept (IL-1 trap)
• Used in patients with contraindications to all standard therapies or refractory gout
• MOA: Block IL-1β, the central inflammatory mediator in the gouty cascade

---

7. DRUG SUMMARY TABLE

---

8. KEY HIGH-YIELD FACTS

---

Sources: Robbins & Kumar Basic Pathology; Katzung's Basic and Clinical Pharmacology, 16th Ed., Chapter 36; Lippincott Illustrated Reviews: Pharmacology; Grainger & Allison's Diagnostic Radiology; Comprehensive Clinical Nephrology, 7th Ed.

---

Etiology of Gout — In Short

---

1. Underexcretion (>90% of cases)

• Chronic kidney disease (↓ GFR)
• Hypertension, obesity, metabolic syndrome
• Lead nephropathy (saturnine gout)
• Hyperparathyroidism, hypothyroidism
• Lactic acidosis / ketoacidosis (lactate/ketones compete with urate at URAT1 transporter)

---

2. Overproduction (<10% of cases)

• Myeloproliferative / lymphoproliferative disorders
• Haemolytic anaemia
• Psoriasis
• Tumour lysis syndrome (chemotherapy)

• Red meat, organ meat, shellfish (purine-rich)
• Beer and alcohol (purine content + ↑ lactate)
• High-fructose corn syrup (↑ purine nucleotide catabolism)

---

Summary

— Goldman-Cecil Medicine; Fitzpatrick's Dermatology; Lippincott Biochemistry, 8th Ed.; Washington Manual of Medical Therapeutics