Cytotoxic Chemotherapies and Clinical Toxicity

Comprehensive vocabulary terms and definitions covering cytotoxic chemotherapy drugs, their mechanisms, resistance, and associated clinical toxicities.

Methotrexate (MTX)

A folic acid antagonist that inhibits dihydrofolate reductase ($DHFR$), preventing the production of folates ($THF$) and dTMP, which results in inhibited DNA synthesis and apoptosis during the $S$ phase.

Leucovorin

An agent used to decrease methotrexate toxicity by bypassing $DHFR$ inhibition and resuming folate production.

5-fluorouracil (5-FU)

A pyrimidine ($T$) analog and prodrug activated to $5\text{-FdUMP}$, which inhibits thymidylate synthase ($TS$) to block DNA synthesis and induce apoptosis in the $S$ phase.

Cyclophosphamide (CPA)

A nitrogen mustard prodrug that is activated to phosphoramide mustard, producing interstrand crosslinks in DNA that cause apoptosis at any time in the cell cycle.

Acrolein

A metabolic byproduct of cyclophosphamide that builds up in the bladder and causes hemorrhagic cystitis.

MESNA

A drug concentrated in the bladder used to detoxify acrolein and reduce the risk of hemorrhagic cystitis during cyclophosphamide therapy.

Aldehyde dehydrogenase (ALDH)

An enzyme that inactivates the cyclophosphamide metabolite $4\text{-OH-CPA}$, providing a mechanism of resistance in hematopoietic-intestinal stem cells.

Doxorubicin

An anthracycline and topoisomerase inhibitor that causes $dsDNA$ breaks by inhibiting $Topo II$, intercalates into DNA, and generates reactive $OH$ radicals.

Dexrazoxane

An iron-chelating cardioprotectant used to decrease the risk of cardiotoxicity associated with doxorubicin therapy.

Vincristine

A vinca alkaloid that blocks microtubule polymerization (assembly), leading to mitotic arrest and apoptosis; it is specifically associated with peripheral neuropathy.

Vinblastine

A vinca alkaloid that blocks microtubule polymerization and is primarily associated with myelosuppression and neutropenia (marrow "blasts").

Paclitaxel

A taxane drug that blocks microtubule depolymerization (disassembly), preventing mitosis and leading to apoptosis.

Tamoxifen

An antiestrogen hormonal therapy that binds to estrogen receptors in $ER\text{-positive}$ tumors, blocking native hormones from stimulating gene expression.

Myelosuppression

Bone marrow suppression, the most common dose-limiting toxicity of chemotherapy, characterized by anemia, increased infection risk, and bleeding risk.

Nadir

The point of lowest blood cell count after chemotherapy, typically occurring at $9$ days with recovery by $21$ days, or at $30$ days with recovery by $49$ days.

Colony stimulating factors

Treatments used to stimulate specific cell lines in the bone marrow to proliferate following chemotherapy-induced myelosuppression.

Stomatitis - Mucositis

Inflammation and ulceration of the oral mucosa caused by the high proliferation rate of oral cells; common with drugs like cyclophosphamide, cisplatin, $MTX$, $5\text{-FU}$, and doxorubicin.

Vesicant Reactions

Severe tissue injuries, similar to burns, resulting from the extravasation of drugs such as vinblastine, doxorubicin, and vincristine.

Extravasation

The accidental leakage of intravenous drugs into the surrounding tissue, which must be avoided to prevent painful necrotic lesions during chemotherapy.

Paresthesia

A numb or tingling sensation resulting from peripheral nervous system neurotoxicity following chemotherapy.

Ileus

A lack of intestinal contraction caused by chemotherapy-induced autonomic nervous system neurotoxicity, often manifesting as constipation.

Somnolence

A state of sleepiness or drowsiness categorized as a central nervous system toxic effect of chemotherapy.