SAQs – Describe the MoA, Adverse Effects & Therapeutic Uses of – 1. ***** Alkylating Agents 2. ***** Cisplatin 3. ***** Methotrexate 4. ***** Purine antagonists 5. ***** Vinca alkaloids 6. ***** Drugs used to Ameliorate Toxicities due to Anti-Cancer Drugs

Reading File

This set covers six high-yield chemotherapy SAQs:

Alkylating agents
Examples, DNA cross-linking mechanism, class toxicities, and major cancer indications.
Cisplatin
Platinum-DNA cross-links, characteristic nephrotoxicity, ototoxicity, neuropathy, severe emesis, and its use in solid tumors.
Methotrexate
Dihydrofolate reductase inhibition, effects on thymidylate/purine synthesis, toxicity profile, leucovorin rescue, and uses in cancers and autoimmune disease.
Purine antagonists
Mainly 6-mercaptopurine, thioguanine, fludarabine, cladribine and related drugs: nucleotide synthesis inhibition, adverse effects, and leukemia indications.
Vinca alkaloids
Vincristine/vinblastine inhibition of microtubule polymerization during M phase, contrasting toxicities, and clinical uses.
Drugs that ameliorate anticancer-drug toxicities
Leucovorin, mesna, dexrazoxane, amifostine, G-CSF/GM-CSF, erythropoietin, antiemetics, allopurinol/rasburicase, and others.

High-level framework: Most cytotoxic anticancer drugs damage rapidly dividing cells, so dose-limiting effects commonly include myelosuppression, mucositis, alopecia, infertility, and teratogenicity. The highest-yield SAQ approach is: mechanism -> 3-5 signature adverse effects -> 3-5 main uses -> toxicity-preventing antidote, if applicable.

Which topic should I write out first in full SAQ format?

Write all six topics as exam-ready SAQ answers

Reading File

Finding Sources

Searching PubMed

antineoplastic drug toxicity prevention

Searching the Web

NCI chemotherapy side effects cisplatin methotrexate vincristine anticancer toxicity prevention

Finding Sources

Reading File

Reading Web Page

https://www.cancer.gov/about-cancer/treatment/drugs/related-…

1. Alkylating Agents

Examples:
Nitrogen mustards: cyclophosphamide, ifosfamide, chlorambucil, melphalan, mechlorethamine
Alkyl sulfonate: busulfan
Nitrosoureas: carmustine, lomustine, streptozocin
Triazenes: dacarbazine, temozolomide
Others: procarbazine, thiotepa, mitomycin-C

Mechanism of action

They are cell cycle-nonspecific (CCNS) cytotoxic drugs, although rapidly dividing cells are more susceptible.
They form reactive electrophilic intermediates that covalently alkylate DNA, particularly at the N7 position of guanine.
This causes:
- Intra-strand and inter-strand DNA cross-linking
- Abnormal base pairing
- DNA strand breaks
- Inhibition of DNA replication and transcription
- Cell death by apoptosis
Nitrosoureas are highly lipid-soluble and cross the blood-brain barrier.

Adverse effects

Common effects

Bone marrow suppression
Nausea, vomiting, mucositis
Alopecia
Gonadal dysfunction, infertility, teratogenicity
Secondary malignancy, particularly acute myeloid leukemia and myelodysplastic syndrome

Characteristic toxicities

Drug	Important toxicity
Cyclophosphamide	Hemorrhagic cystitis due to acrolein, SIADH, cardiotoxicity at high dose
Ifosfamide	Hemorrhagic cystitis, encephalopathy, renal tubular toxicity
Busulfan	Severe and prolonged myelosuppression, pulmonary fibrosis, hyperpigmentation, seizures
Carmustine/lomustine	Delayed cumulative myelosuppression; pulmonary toxicity
Mechlorethamine	Severe vesicant injury on extravasation
Melphalan	Marked myelosuppression
Procarbazine	Myelosuppression, disulfiram-like reaction, interaction with tyramine and serotonergic drugs
Temozolomide/dacarbazine	Myelosuppression, nausea and vomiting

Therapeutic uses

Leukemias and lymphomas: cyclophosphamide, chlorambucil, melphalan, busulfan.
Multiple myeloma: melphalan, cyclophosphamide.
Breast cancer: cyclophosphamide.
Ovarian cancer: cyclophosphamide, melphalan.
Testicular cancer and sarcomas: ifosfamide, cyclophosphamide.
Hodgkin lymphoma: procarbazine in combination regimens.
Brain tumors: carmustine, lomustine, temozolomide.
Conditioning before bone marrow transplantation: busulfan, cyclophosphamide.
Cyclophosphamide is also used as an immunosuppressant in severe autoimmune disease.

2. Cisplatin

Mechanism of action

Cisplatin is a platinum coordination complex with alkylating-agent-like action.
Inside the cell, chloride is displaced by water, generating reactive platinum species.
These bind mainly to the N7 position of guanine and form intra-strand and inter-strand DNA cross-links.
DNA replication and transcription are inhibited, leading to apoptosis.
It is cell cycle-nonspecific.

Adverse effects

Mnemonic: “Cisplatin causes N-V-O-T”

Nephrotoxicity: dose-limiting proximal tubular injury, reduced GFR, magnesium and potassium wasting.
Very severe nausea and vomiting.
Ototoxicity: tinnitus and irreversible high-frequency hearing loss.
Toxic peripheral neuropathy: sensory neuropathy.

Other effects:

Hypomagnesemia, hypokalemia
Mild to moderate myelosuppression
Hypersensitivity reactions
Electrolyte disturbances

Prevention of nephrotoxicity: vigorous IV hydration, maintenance of chloride diuresis, and sometimes amifostine. Cisplatin-related toxicity is a recognized indication for amifostine in oncology practice, as summarized by the NCI drug-toxicity list.

Therapeutic uses

Testicular germ-cell tumors: highly effective, often curative in combination therapy.
Ovarian carcinoma
Bladder carcinoma
Non-small-cell and small-cell lung carcinoma
Head and neck cancers
Cervical carcinoma
Gastric, esophageal, pancreatic and other solid tumors in combination regimens.

3. Methotrexate

Mechanism of action

Methotrexate is a folic acid analogue and an antimetabolite.
It competitively inhibits dihydrofolate reductase (DHFR).
This prevents conversion of dihydrofolate to tetrahydrofolate.
Lack of tetrahydrofolate inhibits:
- Formation of thymidylate, required for DNA synthesis
- De novo purine synthesis
It is therefore predominantly S-phase specific.
Intracellular polyglutamation prolongs its intracellular action.

Adverse effects

Bone marrow suppression: anemia, leukopenia, thrombocytopenia
Mucositis, stomatitis, diarrhea
Nausea and vomiting
Hepatotoxicity: raised transaminases, chronic fibrosis/cirrhosis with long-term use
Acute kidney injury due to precipitation of methotrexate/metabolites in renal tubules, especially with high doses
Pneumonitis and pulmonary fibrosis
Alopecia
Teratogenicity and abortifacient effect
Neurotoxicity with intrathecal or high-dose therapy

Prevention and treatment of toxicity

Leucovorin (folinic acid) rescue: bypasses DHFR blockade and protects normal cells.
High-dose methotrexate requires hydration, urinary alkalinization, and serum methotrexate monitoring.
Glucarpidase rapidly degrades methotrexate and is used in severe toxicity with delayed clearance due to renal dysfunction. The NCI toxicity guidance lists glucarpidase for methotrexate toxicity.

Therapeutic uses

Malignancies

Acute lymphoblastic leukemia, including CNS prophylaxis/treatment by intrathecal route
Non-Hodgkin lymphoma
Osteosarcoma, at high dose with leucovorin rescue
Gestational trophoblastic neoplasia and choriocarcinoma
Breast cancer
Head and neck cancers
Bladder cancer, as part of combination regimens

Nonmalignant conditions

Rheumatoid arthritis
Psoriasis and psoriatic arthritis
Severe inflammatory bowel disease in selected patients
Ectopic pregnancy
Medical termination of early pregnancy, with misoprostol

4. Purine Antagonists

Important drugs:
6-Mercaptopurine (6-MP), thioguanine (6-TG), fludarabine, cladribine, pentostatin, nelarabine.

Mechanism of action

A. Thiopurines: 6-mercaptopurine and thioguanine

They are purine analogues.
6-MP is activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to thioinosinic acid.
Thioguanine is converted to thioguanine nucleotides.
Active metabolites:
- Inhibit de novo purine nucleotide synthesis.
- Are incorporated into DNA and RNA.
- Interfere with DNA replication and function.
They are mainly S-phase specific.

B. Purine nucleoside analogues

Fludarabine, cladribine and pentostatin inhibit DNA synthesis and repair, particularly in lymphoid cells.
Fludarabine inhibits DNA polymerase and ribonucleotide reductase.
Cladribine is incorporated into DNA and interferes with DNA synthesis and repair.
Pentostatin inhibits adenosine deaminase, resulting in accumulation of toxic deoxyadenosine metabolites.

Adverse effects

Thiopurines

Dose-related myelosuppression
Nausea, vomiting, mucositis
Hepatotoxicity
Hyperuricemia
Immunosuppression and increased infection risk
Thioguanine may cause hepatic veno-occlusive disease.

Purine nucleoside analogues

Severe myelosuppression
Profound lymphopenia and immunosuppression
Opportunistic infections
Fever and fatigue
Neurotoxicity can occur with high doses of fludarabine.

Important interactions and precautions

6-MP is inactivated partly by xanthine oxidase.
Allopurinol inhibits xanthine oxidase and can markedly increase 6-MP toxicity. Therefore, reduce the 6-MP dose when both are used.
Deficiency of TPMT or NUDT15 predisposes to severe, sometimes fatal myelosuppression with thiopurines.

Therapeutic uses

Drug	Major uses
6-Mercaptopurine	Maintenance treatment of acute lymphoblastic leukemia; immunosuppression as azathioprine derivative
Thioguanine	Acute myeloid leukemia and acute lymphoblastic leukemia
Fludarabine	Chronic lymphocytic leukemia, indolent non-Hodgkin lymphoma
Cladribine	Hairy-cell leukemia; some low-grade lymphoid malignancies
Pentostatin	Hairy-cell leukemia
Nelarabine	T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma

5. Vinca Alkaloids

Drugs: vincristine, vinblastine, vinorelbine, vindesine.

Mechanism of action

Vinca alkaloids bind to beta-tubulin.
They inhibit polymerization of tubulin and prevent microtubule assembly.
This disrupts formation of the mitotic spindle.
Cells are arrested in metaphase, hence these drugs are M-phase specific.
Microtubule-dependent intracellular transport is also impaired.

Adverse effects

Toxicity	Vincristine	Vinblastine
Peripheral neuropathy	Severe and dose-limiting	Less prominent
Myelosuppression	Minimal or mild	Severe and dose-limiting
Autonomic neuropathy	Constipation, paralytic ileus, urinary retention	May occur but less common
SIADH	Can occur	Less common
Alopecia	Common	Common
Vesicant injury on extravasation	Yes	Yes

Other important adverse effects

Cranial nerve palsies, foot drop, jaw pain, neuropathic pain with vincristine.
Vincristine must never be given intrathecally, as this causes rapidly fatal neurotoxicity.
Hepatic dysfunction requires dose adjustment because these drugs are metabolized and excreted mainly through the hepatobiliary route.

Therapeutic uses

Vincristine

Acute lymphoblastic leukemia
Hodgkin and non-Hodgkin lymphomas
Wilms tumor
Neuroblastoma
Rhabdomyosarcoma
Ewing sarcoma
Multiple myeloma
Used in combinations such as CHOP and various ALL protocols.

Vinblastine

Hodgkin lymphoma
Non-Hodgkin lymphoma
Testicular germ-cell tumors
Breast cancer
Kaposi sarcoma
Histiocytic disorders

Vinorelbine

Non-small-cell lung carcinoma
Metastatic breast cancer

6. Drugs Used to Ameliorate Toxicities Due to Anticancer Drugs

Drug/supportive measure	Toxicity prevented or treated	Main mechanism/use
Leucovorin (folinic acid)	Methotrexate toxicity	Bypasses DHFR blockade and rescues normal cells; also enhances 5-fluorouracil action
Glucarpidase	Severe high-dose methotrexate toxicity with renal failure/delayed elimination	Enzymatically converts methotrexate into inactive metabolites
Mesna	Hemorrhagic cystitis due to cyclophosphamide and ifosfamide	Binds and detoxifies acrolein in urine
Dexrazoxane	Anthracycline cardiotoxicity, especially doxorubicin	Iron chelation and reduction of free-radical-mediated cardiac damage; also used for anthracycline extravasation
Amifostine	Cisplatin nephrotoxicity; radiation-induced xerostomia	Cytoprotective free-radical scavenger, preferential uptake in normal tissues
G-CSF: filgrastim, pegfilgrastim	Chemotherapy-induced neutropenia/febrile neutropenia	Stimulates neutrophil production
GM-CSF: sargramostim	Myelosuppression	Stimulates granulocyte and macrophage progenitors
Erythropoietin/darbepoetin	Chemotherapy-associated anemia in selected patients	Stimulates erythropoiesis
Palifermin	Severe oral mucositis, especially after intensive therapy/stem-cell transplantation	Keratinocyte growth factor that promotes mucosal epithelial repair
5-HT3 antagonists: ondansetron, granisetron, palonosetron	Chemotherapy-induced nausea and vomiting	Block serotonin 5-HT3 receptors
NK1 antagonists: aprepitant, fosaprepitant	Delayed and highly emetogenic chemotherapy-induced vomiting	Block substance P/neurokinin-1 receptors
Dexamethasone and olanzapine	Chemotherapy-induced nausea and vomiting	Used in antiemetic combinations
Allopurinol	Tumor lysis syndrome, especially prevention	Inhibits xanthine oxidase and reduces uric acid production
Rasburicase	Established hyperuricemia in tumor lysis syndrome	Converts uric acid to soluble allantoin
Hydration and urine alkalinization	High-dose methotrexate nephrotoxicity	Enhances renal elimination and prevents tubular precipitation
Sodium thiosulfate	Selected platinum toxicities, including cisplatin-associated ototoxicity in some settings	Binds/inactivates platinum compounds

Very high-yield antidote pairs

Methotrexate -> leucovorin
Cyclophosphamide/ifosfamide -> mesna
Doxorubicin/daunorubicin -> dexrazoxane
Cisplatin -> amifostine plus hydration
High-dose methotrexate with delayed elimination -> glucarpidase
Tumor lysis syndrome -> allopurinol or rasburicase
Chemotherapy-induced neutropenia -> filgrastim/pegfilgrastim

The NCI supportive-drug reference also lists amifostine for cisplatin toxicity, dexrazoxane for doxorubicin toxicity, mesna for hemorrhagic cystitis, glucarpidase for methotrexate toxicity, rasburicase for tumor lysis syndrome, palifermin for mucositis, and G-CSF preparations for neutropenia.

This is a shared conversation. Sign in to Orris to start your own chat.