Alkylating Agents and Platinum

Alkylating agents are cell cycle–independent antineoplastic drugs that work primarily by binding alkyl groups to various parts of DNA. The overall action produces cross-linking of DNA, leading to inhibition of DNA replication and DNA damage. The general effect is cancer (CA) cell death. The subgroups of drugs are nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, ethylenimines, and methylmelamines. Platinum coordination complexes belong to the group of alkylating agents by producing the same effect, but their mechanism is via formation of covalent metal adducts with DNA. Myelosuppression and toxicity to organ systems such as the kidneys, liver, and lungs are common adverse reactions.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Alkylating agents

Alkylating agents are antineoplastic drugs that attach an alkyl group onto DNA to cause cancer (CA) cell death.

  • Have a cytotoxic effect on cells via addition of an alkyl group to various cellular constituents:
    • A major site of alkyl group: N7 position of guanine
    • DNA code is misread with alkylation process → DNA breakage → inhibited DNA, RNA, and protein synthesis
    • Alkylating agents are not cell cycle specific, but they are most effective in late G1 and S phase.
  • Platinum coordination complexes:
    • Classified under alkylating agents, though their action is not the alkylation of DNA
    • These agents form covalent metal adducts with DNA, producing an effect similar to that of alkylating agents. 
  • Alkylating agents affect all cells, primarily those that are rapidly dividing. 
    • CA cells are one of the most rapidly dividing cells.
    • Other, normal cells that undergo frequent cell division are adversely affected, as seen in:
      • Hematopoietic cells → anemia, pancytopenia
      • Reproductive cells → amenorrhea, ↓ spermatogenesis
      • Hair cells → alopecia
      • GI tract → damaged intestinal mucosa

Types of alkylating agents

  • Nitrogen mustards
  • Nitrosoureas
  • Alkyl sulfonates
  • Triazenes
  • Ethylenimine and methylmelamines
  • Platinum coordination complexes

Nitrogen Mustards

General description

  • Nitrogen mustards contain chloroethylamine groups.
  • Drugs in this class:
    • Chlorambucil
    • Cyclophosphamide
    • Ifosfamide
    • Melphalan
    • Bendamustine
  • Mechanism of action: forms DNA cross-links, leading to inhibition of DNA synthesis and function

Chlorambucil

  • Pharmacokinetics:
    • Rapid GI absorption (↓ with food)
    • 99% protein bound
    • Hepatic metabolism to phenylacetic acid mustard
    • Half-life: approximately 1.5 hours
    • Excretion: urine
  • Indications (labeled):
    • CLL
    • Hodgkin lymphoma (HL)
    • Non-Hodgkin lymphoma (NHL)
  • Adverse effects:
    • Myelosuppression
    • Immunosuppression
    • Nausea, vomiting
    • Hepatotoxicity
    • Pulmonary toxicity
    • 2-degree malignancy
    • Infertility
    • Teratogenicity
    • Seizures

Cyclophosphamide

  • Pharmacokinetics:
    • Oral, IV
    • Good oral absorption
    • 20% protein binding
    • Hepatic metabolism
    • Half-life: 3–12 hours IV
    • Excretion: urine
  • Indications (labeled):
    • ALL, AML
    • CLL, CML
    • HL
    • NHL
    • Multiple myeloma (MM)
    • Breast and ovarian CA
    • Neuroblastoma, retinoblastoma
    • Nephrotic syndrome
  • Adverse effects:
    • Nausea, vomiting
    • Myelosuppression
    • Immunosuppression
    • Hepatotoxicity
    • Pulmonary toxicity
    • 2-degree malignancy
    • Infertility
    • Teratogenicity
    • Cardiotoxicity
    • Renal toxicity
    • Bladder toxicity (to ↓ hemorrhagic cystitis: ↑ hydration + mesna)
    • Alopecia
    • SIADH
Chemical structure of cyclophosphamide

Chemical structure of cyclophosphamide

Image: “Cyclophosphamide structure” by Mysid. License: Public Domain

Ifosfamide

  • Pharmacokinetics:
    • Minimal protein binding
    • Hepatic metabolism
    • Half-life: approximately 15 hours (high dose)
    • Excretion: urine
  • Indication (labeled): testicular CA
  • Adverse effects:
    • Nausea, vomiting
    • Myelosuppression
    • Immunosuppression
    • Hepatotoxicity
    • Pulmonary toxicity
    • 2-degree malignancy
    • Infertility
    • Teratogenicity
    • CNS toxicity
    • Cardiotoxicity
    • Hemorrhagic cystitis (↓ by mesna)
    • Nephrotoxicity

Melphalan

  • Pharmacokinetics:
    • Oral absorption is variable.
    • Up to 60% bound to albumin
    • Hepatic metabolism
    • Half-life: 
      • Approximately 75 mins (IV)
      • 1.5 hours (oral)
    • Excretion: 
      • Oral through feces
      • IV through urine
  • Indications (labeled):
    • MM
    • Ovarian CA
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting, and other GI toxicities
    • Hepatotoxicity
    • Pulmonary toxicity
    • Secondary malignancy
    • Extravasation

Bendamustine

  • Produces single- and double-stranded DNA breaks
  • Pharmacokinetics:
    • IV
    • Up to 96% protein bound
    • Hepatic metabolism
    • Excretion: feces, urine
  • Indications (labeled):
    • CLL
    • NHL
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Hepatotoxicity
    • Extravasation
    • Dermatologic toxicity
    • Secondary malignancy
    • Tumor lysis syndrome (TLS)

Contraindications and drug interactions

  • General contraindications:
    • Hypersensitivity to the agent is a common contraindication.
    • Due to the toxic effects of the drugs, they are not advised when adverse effects are severe.
    • Active infection
    • Severe myelosuppression
    • In some cases, severe hepatic or renal impairment
  • General drug interactions with vaccines:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
  • Specific drug interactions:
    • Cyclophosphamide:
      • ↑ Pulmonary toxicity of amiodarone
      • ↑ Cardiotoxicity with pentostatin
      • ↑ Cardiotoxic effects of anthracyclines
    • Ifosfamide: ↑ anticoagulant effect of vitamin K antagonists
    • Melphalan: ↑ pulmonary toxicity of carmustine

Nitrosoureas

General description

  • Nitrosoureas are chemotherapy agents that include a nitroso and urea group.
  • Agents undergo transformation to metabolites with alkylating and carbamyolating properties.
  • Highly lipid soluble: can cross the blood–brain barrier (BBB), making this class of medications useful in treating CNS malignancies
  • Drugs in this class:
    • Carmustine
    • Lomustine
  • Mechanism of action: forms DNA cross-links
    • Alkylation on the N7 position of guanine in DNA and on the O6 position of guanine
    • Prevents DNA replication and transcription

Carmustine

  • Pharmacokinetics:
    • IV, implant
    • Crosses BBB, reaching > 50% of plasma levels
    • Hepatic metabolism
    • Excretion: urine
  • Indications (labeled):
    • Brain tumors
    • NHL
    • HL
    • MM
  • Adverse effects:
    • Myelosuppression
    • Cardiovascular: arrhythmia, tachycardia
    • GI: nausea, vomiting, mucositis
    • Hepatic: ↑ transaminases, ↑ alkaline phosphatase (ALP)
    • Renal: azotemia, renal failure
    • Respiratory: interstitial pneumonitis
    • Secondary malignancy
Chemical structure of carmustine

Chemical structure of carmustine

Image: “Carmustine” by Fvasconcellos. License: Public Domain

Lomustine

  • Pharmacokinetics:
    • Oral
    • Crosses BBB
    • Hepatic metabolism
    • Excretion: urine
  • Indications (labeled):
    • Brain CA
    • HL
  • Adverse effects:
    • Myelosuppression
    • GI: nausea, vomiting, mucositis
    • Hepatic: ↑ transaminases, ↑ ALP
    • Renal: azotemia, renal failure
    • Respiratory: pulmonary fibrosis
    • Secondary malignancy
Chemical structure of lomustine

Chemical structure of lomustine

Image: “Lomustine” by Fvasconcellos. License: Public Domain

Contraindications and drug interactions

  • General contraindications:
    • Hypersensitivity to the agent is a common contraindication.
    • Due to toxic effects of the drugs, they are not advised when adverse effects are severe.
  • General drug interactions with vaccines:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)

Alkyl Sulfonates

General description

  • Alkyl sulfonates are alkyl esters of sulfonic acid.
  • Drug in this class: busulfan
  • Mechanism of action: forms DNA cross-links 
    • Alkylation on the N7 position of guanine
    • Inhibition of DNA synthesis and function

Busulfan

  • Pharmacokinetics:
    • IV and oral
    • Rapid absorption
    • Crosses BBB
    • Hepatic metabolism
    • Half-life: 2.5 hours
    • Excretion: majority through the urine
  • Indications (labeled): CML
  • Adverse effects:
    • Myelosuppression
    • Cardiovascular: hypertension, chest pain, cardiac tamponade
    • GI: nausea, vomiting
    • Hepatic sinusoidal obstruction syndrome
    • Pulmonary: bronchopulmonary dysplasia with pulmonary fibrosis (“busulfan lung”: cough, dyspnea, ↓ pulmonary capacity) 
    • Secondary malignancy
    • Hyperpigmentation
    • Adrenal insufficiency
  • Contraindications: 
    • Hypersensitivity to the drug
    • Without confirmed CML
  • Drug Interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
    • Acetaminophen: ↓ busulfan clearance
    • Phenytoin: ↑ busulfan clearance
Chemical structure of busulfan

Chemical structure of busulfan

Image: “Busulfan” by Fvasconcellos. License: Public Domain

Triazines

General description

  • Triazines are nitrogen heterocycles used as chemotherapy, frequently in the treatment of brain CA or lymphoma.
  • Drugs in this drug class:
    • Procarbazine
    • Dacarbazine 
    • Temozolomide
  • Mechanism of action: inhibition of DNA synthesis and function by alkylation 

Procarbazine

  • In addition to alkylation, procarbazine inhibits transmethylation of methionine into tRNA.
  • Pharmacokinetics:
    • Oral
    • Rapid absorption
    • Crosses BBB
    • Hepatic metabolism
    • Half-life: approximately 1 hour
    • Excretion: urine
  • Indication (labeled): HL
  • Adverse effects:
    • Myelosuppression
    • CNS toxicity (confusion, neuropathies)
    • Pulmonary toxicity
    • Hepatotoxicity
    • Nausea, vomiting
    • Disulfiram-like reaction
    • Hemolysis
    • Hemorrhage
    • Secondary malignancy
    • Infertility
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe myelosuppression
    • Alcohol intake (disulfiram effect)
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
    • Avoid the following, as procarbazine metabolite is a weak monoamine oxidase inhibitor (MAOI) (an interaction such as acute hypertension can occur): 
      • MAOIs
      • Sympathomimetic agents
      • Antihistamines
      • Tricyclic antidepressants (TCAs)
      • Foods high in tyramine content
Chemical structure of procarbazine

Chemical structure of procarbazine

Image: “Procarbazine” by Fvasconcellos. License: Public Domain

Dacarbazine

  • Alkylation (methylation) leads to DNA double strand breaks.
  • Pharmacokinetics:
    • IV
    • Hepatic metabolism
    • Excretion: urine
  • Indications (labeled):
    • HL
    • Metastatic melanoma
  • Adverse effects:
    • Myelosuppression
    • Hepatotoxicity
    • Secondary malignancy
    • Teratogenicity
    • Alopecia
    • Nausea, vomiting
  • Contraindications: hypersensitivity to the drug
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)

Temozolomide

  • Temozolomide is less effective against tumors that express the MGMT gene (codes for an alkyltransferase protein that can repair sites of alkylation/methylation).
  • Conversely, silencing of the MGMT gene makes temozolomide active against the tumor cells. 
  • Also a weak MAOI
  • Pharmacokinetics:
    • IV, oral
    • Metabolism: hydrolysis
    • Half-life: 1.8 hours
    • Excretion: urine
  • Indications (labeled):
    • Anaplastic astrocytoma
    • Glioblastoma multiforme (GBM)
  • Adverse effects:
    • Myelosuppression
    • Hepatotoxicity
    • Secondary malignancy
    • Pneumocystis pneumonia (PCP): Provide prophylaxis.
    • Hepatotoxicity
    • Nephrotoxicity
  • Contraindications:
    • Hypersensitivity
    • Severe myelosuppression
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines
    • Avoid the following (given weak MAOI activity):
      • Sympathomimetic drugs 
      • TCAs
      • Antidepressants

Ethylenimines and Methylmelamines

General description

  • Medications in this drug class:
    • Thiotepa 
    • Altretamine
  • Mechanism of action: forms DNA cross-links via alkylation reaction
    • Inhibition of DNA synthesis and function
    • Major site of alkyl group: N7 position of guanine

Thiotepa

  • Contains 3 ethylenimine groups 
  • Pharmacokinetics:
    • IV, intrathecal
    • Metabolism: hepatic via the cytochrome P450 system
    • Excretion: urine
  • Indications (labeled): 
    • Beta thalassemia
    • Off-label: conditioning regimen before stem cell transplantation, leptomeningeal metastasis
  • Adverse effects:
    • Myelosuppression 
    • Nausea and vomiting
    • Hepatotoxicity
    • CNS toxicity (e.g., headache, confusion, encephalopathy)
    • Dermatologic toxicity (e.g., pruritus, discoloration, blistering)
    • Hepatic sinusoidal obstruction syndrome
    • Secondary malignancy
  • Contraindications: hypersensitivity to the drug
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
Chemical structure of thiotepa

Chemical structure of thiotepa

Image: “ThioTEPA” by Fvasconcellos. License: Public Domain

Altretamine

  • Similar to triethylenemelamine in structure
  • Pharmacokinetics:
    • Oral
    • Hepatic metabolism
    • Half-life: 4–10 hours
    • Excretion: urine
  • Indication (labeled): ovarian CA
  • Adverse effects:
    • Myelosuppression
    • GI: nausea, vomiting
    • CNS toxicity and peripheral neuropathy
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe neurologic toxicity
    • Myelosuppression
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines (avoid live vaccines)
    • Intake with MAOIs can cause orthostatic hypotension.

Platinum Coordination Complexes

General description

  • Cell cycle–nonspecific drugs with broad anticancer activity
  • Medications in this drug class:
    • Cisplatin 
    • Carboplatin 
    • Oxaliplatin
  • Mechanism of action:
    • Covalently binds DNA (forming intrastrand and interstrand cross-links), with cytotoxic effects similar to alkylating agents
    • Inhibits DNA replication

Cisplatin

  • Pharmacokinetics:
    • IV
    • 90% proteinbinding
    • Half-life: 20–30 minutes in adults
    • Excretion: renal
  • Indications (labeled):
    • Bladder CA
    • Ovarian CA
    • Testicular CA
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Peripheral neuropathy
    • Nephrotoxicity (prehydration advised to ↓ risk of kidney damage)
    • Secondary malignancy 
    • ↑ Liver enzymes
    • Ototoxicity
    • TLS
    • May exacerbate myasthenia gravis (MG)
  • Contraindications: hypersensitivity to the drug
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines
    • Loop diuretics: ↑ nephrotoxicity of cisplatin
Chemical structure of cisplatin

Chemical structure of cisplatin

Image: “Cisplatin-stereo” by Benrr101. License: Public Domain

Carboplatin

  • 2nd-generation platinum analog, carrying less GI and renal toxicity than cisplatin
  • Pharmacokinetics:
    • IV
    • Minimal hepatic metabolism
    • Half-life: 3–6 hours (normal renal function)
    • Excretion: urine (approximately 70% as carboplatin)
  • Indication (labeled): ovarian CA
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Peripheral neuropathy
    • Nephrotoxicity
    • Secondary malignancy 
    • ↑ Liver enzymes
    • Ototoxicity
    • Vision loss (high doses)
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe myelosuppression
    • Preexisting renal impairment
    • Bleeding
  • Drug interactions:
    • ↓ Therapeutic effect of inactivated and live vaccines
    • ↑ Toxic effect of live vaccines
Chemical structure of carboplatin

Chemical structure of carboplatin

Image: “Carboplatin-skeletal” by catclock. License: Public Domain

Oxaliplatin

  • 3rd-generation platinum analog
  • Pharmacokinetics:
    • IV
    • > 90% protein binding
    • Enzymatic metabolism
    • Excretion: urine
  • Indications: colorectal CA (CRC)
  • Adverse effects:
    • Myelosuppression
    • Nausea, vomiting
    • Nephrotoxicity
    • Neuropathy
    • Cardiotoxicity
    • Hepatotoxicity
    • Bleeding
    • Pulmonary toxicity
    • Rhabdomyolysis 
  • Contraindications: 
    • Hypersensitivity to the drug
    • Preexisting peripheral neuropathy with impaired function
Chemical structure of oxaliplatin

Chemical structure of oxaliplatin

Image: “Oxaliplatin-2D-skeletal” by Benjah-bmm27. License: Public Domain

Comparison with Other Chemotherapeutic Agents

Chemotherapy comparison

Various chemotherapy drugs and their effects on the cell cycle

Image by Lecturio.
Table: Comparison of the cell cycle–independent chemotherapy drugs
Drug classMechanism
Antitumor antibiotics:
  • Dactinomycin
  • Mitomycin
Intercalation between bases leading to blockage of DNA or RNA synthesis, and prevention of DNA replication
Anthracyclines
  • Inhibition of topoisomerase II
  • DNA intercalation, leading to DNA and RNA inhibition
  • Promotion of reactive oxygen species formation
Alkylating agents
  • ↓ DNA synthesis due to alkylation of DNA
  • ↓ DNA replication, protein synthesis

References

  1. Chu, E. (2021). Cancer chemotherapy. In Katzung, BG., & Vanderah, TW (Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603422
  2. Gold, JM, & Raja, A. (2021). Cisplatin. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK547695/
  3. Katzung, B, & Trevor, A. (2020). Basic and Clinical Pharmacology, 15e. McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250593594
  4. Ogino, MH, & Tadi, P. (2021). Cyclophosphamide. StatPearl. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK553087/
  5. Patel, R, & Tadi, P. (2021). Busulfan. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK555986/
  6. Altretamine. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/altretamine-drug-information
  7. Bendamustine. (2021). Bendamustine. UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/bendamustine-drug-information
  8. Busulfan. (2021). UpToDate. Retrieved Sept 19, 2021 from, https://www.uptodate.com/contents/busulfan-drug-information
  9. Carboplatin. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/carboplatin-drug-information
  10. Cisplatin. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/cisplatin-drug-information
  11. Cyclophosphamide. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/cyclophosphamide-drug-information
  12. Oxaliplatin. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/oxaliplatin-drug-information
  13. Thiotepa. (2021). UpToDate. Retrieved Sept 19, 2021, from https://www.uptodate.com/contents/thiotepa-drug-information
  14. Wellstein, A, Giaccone, G, Atkins, MB, & Sausville, EA. (2017). Cytotoxic drugs. In Brunton, LL, Hilal-Dandan, R, & Knollmann, BC (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172486857

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details