Discuss the antiviral spectrum and therapeutic uses of acyclovir. Doxorubicin is an antibiotic. Enumerate its role in cancer…

(a)(i) Acyclovir: antiviral spectrum and therapeutic uses

Acyclovir is a guanosine analogue prodrug. It is first phosphorylated by viral thymidine kinase, which gives it selectivity, and then by host kinases to acyclovir triphosphate. This inhibits viral DNA polymerase and, when incorporated, terminates the growing DNA chain.

Spectrum: HSV-1 and HSV-2 (most sensitive), VZV (needs higher doses), with weak activity against EBV and little against CMV, which lacks thymidine kinase.

Therapeutic uses:

• herpes labialis, genital herpes (treatment and suppression) and herpetic keratitis (topical);
• HSV encephalitis and neonatal herpes, where intravenous acyclovir is the drug of choice;
• chickenpox and herpes zoster, especially in adults and immunocompromised patients;
• prophylaxis of HSV/VZV reactivation in transplant and cancer patients.

Valacyclovir is its oral prodrug with better bioavailability. Resistance arises from thymidine-kinase-deficient mutants; foscarnet is then used. Nephrotoxicity (crystalluria) with rapid intravenous doses is the main adverse effect.

(a)(ii) Doxorubicin

Doxorubicin is an anthracycline antibiotic from Streptomyces. It intercalates into DNA, inhibits topoisomerase II and generates free radicals, blocking DNA replication and transcription.

Role in chemotherapy: breast cancer (AC regimen), Hodgkin lymphoma (ABVD), non-Hodgkin lymphoma (CHOP), acute leukaemias, soft-tissue and bone sarcomas, and ovarian, thyroid, gastric and lung cancers.

Adverse effects:

• dose-dependent cardiotoxicity (dilated cardiomyopathy), limited by keeping the cumulative dose below about 450–550 mg/m² and by dexrazoxane;
• myelosuppression, alopecia, mucositis, nausea and vomiting;
• tissue necrosis on extravasation and radiation recall;
• red discoloration of urine.

(b) Hypersensitivity

Hypersensitivity is an exaggerated or inappropriate immune response to an antigen that causes tissue damage. The Gell and Coombs classification has four types:

• Type I (immediate, IgE-mediated): anaphylaxis, bronchial asthma, allergic rhinitis, urticaria, food allergy.
• Type II (antibody-mediated cytotoxic, IgG/IgM): autoimmune haemolytic anaemia, ABO transfusion reaction, Goodpasture syndrome, myasthenia gravis.
• Type III (immune-complex mediated): serum sickness, SLE, post-streptococcal glomerulonephritis, Arthus reaction.
• Type IV (delayed, T-cell mediated): tuberculin reaction, contact dermatitis, granulomas in tuberculosis.

Type I hypersensitivity is a rapid reaction in a sensitised individual. On first exposure, Th2 cells (IL-4, IL-13) drive IgE production, and IgE binds FcεRI on mast cells and basophils. On re-exposure, antigen cross-links IgE, causing degranulation. The immediate phase (minutes) is due to histamine, tryptase, leukotrienes and prostaglandins, which cause vasodilatation, oedema, bronchoconstriction and mucus secretion. The late phase (2–24 hours) is due to eosinophils and Th2 cytokines.

In health, this response protects against helminths and some venoms. In disease, it causes atopy (asthma, allergic rhinitis, eczema, urticaria), food and drug allergy, and life-threatening anaphylaxis.

(c) Cancer and cancer-related genes

Cancer is a disorder of clonal cells with uncontrolled, autonomous growth that invades surrounding tissues and can metastasise. It results from accumulated mutations in four classes of genes:

• Proto-oncogenes/oncogenes: gain-of-function mutations in growth factors, receptors (HER2, EGFR), signal transducers (RAS, BRAF), transcription factors (MYC) and cyclins (cyclin D1) give self-sufficiency in growth signals.
• Tumour suppressor genes: loss-of-function mutations (two hits) in RB (the G1/S checkpoint), TP53 (DNA-damage arrest and apoptosis), APC and NF1 remove the brakes on proliferation.
• Genes regulating apoptosis: overexpression of BCL-2 (follicular lymphoma) or loss of BAX allows abnormal cells to survive.
• DNA repair genes: defects in BRCA1/2 and mismatch-repair genes cause genomic instability and a mutator phenotype.

These changes produce the hallmarks of cancer: sustained proliferation, evasion of growth suppressors and apoptosis, limitless replication (telomerase), angiogenesis, invasion and metastasis, altered metabolism (Warburg effect) and immune evasion.

(d) Case: 50-year-old male, polyuria and polydipsia for 5 years, HbA1c 12%, normal cardiac enzymes, proteinuria

(i) Most likely diagnosis: poorly controlled type 2 diabetes mellitus with diabetic nephropathy. The chest pain with normal cardiac enzymes is probably stable angina or non-cardiac pain, but the macrovascular risk is high.

(ii) Microscopic findings:

• diffuse thickening of the glomerular basement membrane and mesangial matrix expansion (diffuse glomerulosclerosis);
• nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), which is characteristic;
• hyaline arteriolosclerosis of both afferent and efferent arterioles, capsular drops and fibrin caps;
• tubular atrophy, interstitial fibrosis and, in some cases, papillary necrosis or pyelonephritis.

(iii) Pathogenesis: chronic hyperglycaemia causes non-enzymatic glycation of proteins, forming advanced glycation end-products (AGEs). It also activates protein kinase C and the polyol pathway and generates oxidative stress. Glomerular hyperfiltration and intraglomerular hypertension (efferent arteriolar constriction by angiotensin II) injure podocytes, while TGF-β drives matrix accumulation. Clinically, microalbuminuria progresses to overt proteinuria and a falling GFR.

(e) Injury and its age

Injury means any harm, whatever, illegally caused to any person in body, mind, reputation or property (Section 2(14), Bharatiya Nyaya Sanhita, 2023, formerly Section 44 IPC). Medically, a wound is a breach of the continuity of tissues caused by violence. Ageing a wound helps to decide whether it was ante-mortem and to reconstruct events.

Microscopic timeline:

• within minutes to 4 hours: dilated vessels, oedema and margination of neutrophils;
• 4–12 hours: neutrophil infiltration at the wound margin;
• 24–72 hours: neutrophils peak and macrophages appear; epithelial regeneration begins;
• 3–5 days: granulation tissue with fibroblasts and new capillaries; haemosiderin-laden macrophages appear;
• 1–2 weeks: collagen deposition, with haematoidin crystals after about a week;
• weeks to months: mature scar with decreasing vascularity.

Histochemical methods (Raekallio's enzyme histochemistry at the wound margin):

• ATPase and esterase activity rises within about 1 hour;
• aminopeptidase at about 2 hours;
• acid phosphatase at about 4 hours;
• alkaline phosphatase at about 8 hours.

Perls' Prussian blue stain shows haemosiderin from about the third day, and immunohistochemistry (fibronectin within minutes, CD68 macrophages, collagen types III and I) refines the estimate. Correlating these sequential changes gives an approximate age of the injury.