Monograph of Cisplatin

Introduction

Cisplatin is a platinum‑based chemotherapeutic agent that has been a cornerstone of antitumor therapy since its introduction in the early 1970s. The compound is characterized by a square planar geometry, with two ammine ligands and two chloride ligands, which confer both structural stability and reactivity. Over the past five decades, cisplatin has maintained a pivotal role in the treatment of a variety of solid tumors, including testicular, ovarian, bladder, head and neck, lung, and metastatic colorectal cancers. Its inclusion in combination regimens has contributed to improved survival rates in many malignancies.

Learning objectives for this chapter include:

• To describe the chemical and pharmacological properties of cisplatin.
• To elucidate the molecular mechanisms underlying cisplatin’s antitumor activity.
• To analyze the pharmacokinetic profile and factors influencing cisplatin disposition.
• To identify common adverse effects and strategies for mitigation.
• To apply knowledge of cisplatin therapy to clinical scenarios and therapeutic decision‑making.

Fundamental Principles

Core Concepts and Definitions

Platinum coordination chemistry forms the basis of cisplatin’s structure. The central platinum(II) ion is coordinated by two chloride ions and two ammine ligands, yielding a cis configuration that is essential for biological activity. The term “cisplatin” derives from the relative positions of the chloride ligands, which are adjacent (cis) rather than opposite (trans). This spatial arrangement influences the drug’s reactivity with nucleophilic sites in biomolecules.

Theoretical Foundations

Cisplatin’s mechanism of action is rooted in its ability to form covalent adducts with nucleophilic centers on DNA, RNA, and proteins. The drug undergoes aquation—a ligand exchange in which chloride ligands are replaced by water molecules—upon entering the aqueous intracellular environment. The resulting positively charged species reacts preferentially with the N7 position of guanine residues, forming intrastrand cross‑links (typically 1,2‑d(GpG) and 1,2‑d(GpA)). These cross‑links distort the helical structure, impede replication and transcription, and ultimately trigger apoptosis.

Key Terminology

• Aquation – Replacement of chloride ligands by water molecules, increasing reactivity.
• Adduct – Covalent complex formed between cisplatin and a nucleophilic target.
• Intrastrand cross‑link – Covalent bond between adjacent nucleobases on the same DNA strand.
• Nephrotoxicity – Renal damage commonly associated with cisplatin therapy.
• Hepatotoxicity – Liver injury reported in high‑dose cisplatin regimens.
• DNA repair pathways – Cellular processes such as nucleotide excision repair (NER) and mismatch repair (MMR) that influence cisplatin sensitivity.

Detailed Explanation

Molecular Mechanisms and Biological Processes

Upon systemic administration, cisplatin distributes widely throughout the body, with significant accumulation in the kidneys, liver, and bone marrow. The drug’s high plasma protein binding (≈70 %) to albumin and α1‑acid glycoprotein modulates its free fraction and influences tissue penetration. Within the cell, aquation proceeds rapidly; the rate constant is dependent on chloride concentration, with lower extracellular chloride (as seen in the tumor microenvironment) favoring increased aquation and thus heightened cytotoxicity.

Following aquation, cisplatin binds to DNA, forming mono‑ and bis‑adducts. The predominant species is the 1,2‑intrastrand cross‑link between adjacent guanine residues. This adduct introduces a bend of approximately 30° in the DNA helix and distorts base pairing, thereby blocking DNA polymerases and RNA polymerases. The resulting replication fork stalling activates the DNA damage response (DDR), leading to cell cycle arrest in G₁ or G₂ phases, and ultimately apoptosis via p53‑dependent and independent pathways.

Pharmacokinetic Modeling

Cisplatin follows a multi‑compartment pharmacokinetic model, often described by a two‑compartment linear system. The concentration–time profile can be approximated by the equation:

C(t) = C₀ × [e^-k₁ t × m₁ + e^-k₂ t × m₂]

where C₀ represents the initial concentration, k₁ and k₂ are the rate constants for distribution and elimination phases, respectively, and m₁ and m₂ are the respective distribution fractions. The area under the plasma concentration–time curve (AUC) is calculated as:

AUC = Dose ÷ Clearance

Clearance is predominantly renal, with glomerular filtration and tubular secretion contributing to elimination. The effective half‑life (t_1/2) can vary from 5 to 12 hours, depending on patient factors such as renal function and concomitant medications.

Factors Influencing Cisplatin Activity

• Chloride Concentration – Low extracellular chloride enhances aquation and DNA binding.
• pH – Acidic tumor microenvironments favor cisplatin activation.
• DNA Repair Capacity – Deficiencies in NER or MMR genes increase sensitivity.
• Drug‑Drug Interactions – Co‑administration of nephrotoxic agents can amplify renal damage.
• Genetic Polymorphisms – Variations in glutathione S‑transferase (GST) influence detoxification.

Clinical Significance

Relevance to Drug Therapy

Cisplatin remains one of the most effective single agents in oncology, particularly for germ cell tumors in which it achieves cure rates exceeding 80 %. Its utility as a backbone of combination regimens—such as cisplatin‑etoposide for small cell lung cancer, cisplatin‑carboplatin for ovarian cancer, and cisplatin‑paclitaxel for head and neck carcinoma—illustrates its versatility. Dose modifications based on renal function (e.g., using the Cockcroft–Gault equation) are essential to balance efficacy and toxicity.

Practical Applications

Key practical considerations include:

• Pre‑hydration – Administration of isotonic saline (1–1.5 L) before and after cisplatin infusion reduces nephrotoxicity.
• Co‑administration of Diuretics – Loop diuretics (e.g., furosemide) promote diuresis, further protecting renal tubular cells.
• Monitoring – Serial serum creatinine, BUN, and electrolytes (potassium, magnesium) are monitored to detect early renal injury.
• Ototoxicity Surveillance – Audiologic testing is recommended before, during, and after therapy, especially in patients receiving cumulative doses >200 mg/m².
• Toxicity Prophylaxis – Antiemetic regimens (e.g., ondansetron + dexamethasone) mitigate cisplatin‑induced nausea and vomiting.

Clinical Applications/Examples

Case Scenario 1: Testicular Germ Cell Tumor

A 28‑year‑old male presents with a teratoma of the right testis. After orchiectomy, adjuvant chemotherapy with cisplatin‑etoposide is initiated. The standard regimen delivers 100 mg/m² cisplatin IV over 1 hour on days 1, 5, 9, and 13 of a 21‑day cycle. Pre‑hydration with 1 L of 0.9% saline is administered 30 minutes before infusion. Post‑infusion, 1 L of saline is continued for 2 hours. Potassium and magnesium levels are maintained ≥ 4 mmol/L and ≥ 2 mg/dL, respectively, through supplementation. The patient completes three cycles with no evidence of residual disease; the cumulative cisplatin dose is 400 mg/m², below the threshold associated with significant ototoxicity.

Case Scenario 2: Advanced Ovarian Carcinoma

A 62‑year‑old woman with stage IIIc epithelial ovarian cancer undergoes cytoreductive surgery. Post‑operative chemotherapy consists of carboplatin (AUC 5) and paclitaxel (175 mg/m²) every 3 weeks for six cycles. Carboplatin is selected to reduce nephrotoxic risk; however, cisplatin is still considered for platinum‑refractory disease. If cisplatin were to be introduced, dose adjustments for creatinine clearance < 60 mL/min would be mandated, and a lower starting dose (80 mg/m²) would be adopted with careful monitoring.

Case Scenario 3: Small Cell Lung Cancer

A 55‑year‑old smoker is diagnosed with extensive‑stage small cell lung cancer. The standard first‑line therapy comprises cisplatin 50 mg/m² IV on day 1, combined with etoposide 100 mg/m² days 1–3, repeated every 21 days for four cycles. The patient’s baseline serum creatinine is 1.0 mg/dL (estimated GFR ≈ 75 mL/min). The regimen proceeds without dose reduction. During cycle two, mild nausea and vomiting are managed with ondansetron 8 mg IV before infusion and dexamethasone 10 mg IV. No significant nephrotoxicity occurs, and the patient achieves partial response after four cycles.

Summary/Key Points

• Cisplatin is a platinum(II) coordination compound that undergoes aquation to form reactive species capable of producing DNA cross‑links.
• DNA adduct formation disrupts replication and transcription, activating DNA damage responses that culminate in apoptosis.
• The pharmacokinetic profile is characterized by rapid distribution, renal elimination, and a variable half‑life influenced by renal function.
• Nephrotoxicity, ototoxicity, and gastrointestinal toxicity represent the principal adverse effects; pre‑hydration, electrolyte supplementation, and antiemetic prophylaxis are standard mitigation strategies.
• Clinical use of cisplatin remains integral to the management of a broad spectrum of solid tumors, with dosing tailored to organ function and cumulative exposure.

Clinical pearls include diligent monitoring of renal function and electrolytes, early intervention for dehydration, and the use of cisplatin‑sparing regimens in patients with pre‑existing renal impairment. Understanding cisplatin’s mechanistic underpinnings facilitates rational therapeutic decisions and improves patient outcomes in oncology practice.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.