Oncology Drugs: Intro and DNA Modifiers

Vocabulary-style flashcards covering the key mechanisms, toxicities, and classifications of oncology drugs including DNA alkylators, platinum complexes, intercalators, topoisomerase inhibitors, antimetabolites, and antimitotic agents.

Tumor Mutation Burden (TMB)

A measurement where higher levels are generally associated with poorer patient survival but also permit the immune system to better distinguish tumor cells from normal cells via neoantigens, leading to longer survival in patients treated with immune checkpoint inhibitors.

DNA Alkylators

A class of drugs including nitrogen mustards, alkyl sulfonates, and triazenes that contain electrophilic groups that covalently modify DNA to cause crosslinking, triggering apoptosis in a cell-cycle non-specific manner.

Acrolein

A toxic metabolite of cyclophosphamide and ifosfamide that causes hemorrhagic cystitis by covalently modifying cysteine residues of proteins in bladder cells.

Mesna

A rescuing agent used to mitigate the toxicity of acrolein by reacting with it to prevent hemorrhagic cystitis.

Platinum Complexes

Complexes of $\text{Pt}^{2+}$ with two leaving groups ($Cl$ or $O$) and two non-leaving groups ($NH$) in cis-configuration that bind to negatively charged DNA and complex with two Guanine N7 positions to inhibit DNA synthesis.

Amifostine

A prodrug activated by alkaline phosphatase into 2-((aminopropyl)amino)ethanethiol, which scavenges electrophiles and free radicals to protect normal tissues from the toxicity of platin drugs.

DNA Intercalators

Flat, unsaturated, polycyclic molecules that bind to the DNA double helix by inserting between base pairs, distorting the structure and interfering with replication and transcription.

Anthracyclines

A subgroup of DNA intercalators, such as daunorubicin and doxorubicin, which are cell cycle non-specific and are known for being strong vesicants and causing cumulative myocardiotoxicity.

Dexrazoxane

An agent used to mitigate the cardiotoxicity of doxorubicin by chelating with $Fe$ that mediates the generation of reactive oxygen species (ROS).

Liposomal doxorubicin (Doxil)

A nanomedicine formulation (diameter approx. $100\,\text{nm}$) that allows for sustained release and lower toxicity, with preferred distribution into solid tumors due to leaky vasculature.

Etoposide

A Topoisomerase II inhibitor that is mostly G2 phase specific and prevents the re-ligation of DNA strands during decatenation.

Topotecan

A Topoisomerase I inhibitor that is S phase specific and works by cutting and re-ligating one strand of DNA to relieve tension during replication.

Antimetabolites

Analogues of pyrimidines, purines, or folic acid that enter cells via transporters and suppress the synthesis of DNA, RNA, and protein building blocks, typically resulting in S-phase-specific killing.

Methotrexate (MTX)

An antifolate that inhibits dihydrofolate reductase (DHFR), preventing the synthesis of $TMP/TTP$ and causing 'thymineless death'.

Leucovorin

A rescuing agent used in conjunction with antifolates like Methotrexate to mitigate toxicity.

Vinca alkaloids

Large lipophilic antimitotic agents (e.g., vincristine, vinblastine) that interfere with the assembly of microtubules, trapping cells in the M phase.

Taxanes

Antimitotic agents (e.g., paclitaxel) consisting of a 15-member taxane ring that interfere with the disassembly of microtubules, resulting in M phase specific killing.

Abraxane

An albumin-bound formulation of paclitaxel that requires no oil for dissolution, avoids hypersensitivity reactions, and is more tolerable than traditional taxanes.

Vesicants

Agents that cause severe tissue damage or blisters if injected outside of the vein, a characteristic of both anthracyclines and vinca alkaloids.