chemotherapeutic (antineoplastic) agents

What is the general function of chemotherapeutic (antineoplastic) agents according to the summary?

To directly or indirectly inhibit the uncontrolled growth and proliferation of cancer cells. Summary 1

How are chemotherapeutic agents generally classified?

According to their mechanism of action (e.g., alkylating agents, antimetabolites, topoisomerase inhibitors, antibiotics, mitotic inhibitors, protein kinase inhibitors). Summary / Overview 2

Name three common categories of adverse effects associated with chemotherapy mentioned in the summary.

Nausea, vomiting, immunosuppression (myelosuppression), impaired growth of healthy cells (e.g., hair loss, mucositis). (Risk of secondary neoplasms also mentioned). Summary / Overview 3

What is the purpose of administering detoxifying agents alongside certain chemotherapeutics?

To avert preventable side effects (e.g., leucovorin after methotrexate, mesna after cyclophosphamide). Summary / Detoxifying 4

On which cells are chemotherapeutic agents generally most active?

Cells with a high growth fraction, i.e., cells actively undergoing division (includes cancer cells and normal cells like bone marrow/epithelium). Overview / Basics 5

What is the log-kill hypothesis in chemotherapy?

A mathematical model stating that a given chemo dose eliminates a constant fraction of cancer cells, regardless of tumor size. Overview / Basics 6

What is the difference between cell cycle-specific and cell cycle-nonspecific antineoplastic agents?

Cell cycle-specific agents act only during specific phases of the cell cycle (not G0); Cell cycle-nonspecific agents act at any phase, including the resting (G0) phase. Overview / Basics 7

Name two mechanisms by which cancer cells can develop resistance to chemotherapeutic agents.

Mutations/altered expression of targets, increased DNA repair, drug inactivation (e.g., antioxidants), altered apoptosis pathways (e.g., Bcl-2), drug efflux (e.g., MDR1/P-glycoprotein). Overview / Basics 8

Name one advantage of using combination chemotherapy regimens.

Increased log-kill, prevention/counteraction of resistance, targeting dividing & resting cells, synergistic effects allowing lower doses/less toxicity. Overview / Combination 9

What are common routes of administration for chemotherapy besides intravenous?

Oral, intrathecal, and topical application. Overview / Routes 10

When is topical chemotherapy (e.g., 5-FU) typically used?

Used in the treatment of cancerous or precancerous skin lesions (e.g., actinic keratosis, basal cell carcinoma). Overview / Routes 11

What is the goal of intrathecal chemotherapy administration?

To prevent/treat meningeal disseminated diseases (e.g., meningeal leukemia/lymphoma) and potentially avoid cerebral radiation. Overview / Routes 12

Name one chemotherapeutic agent that can be administered intrathecally.

Methotrexate or cytarabine. Overview / Routes 13

Why are many chemotherapeutic agents less effective for treating malignant CNS diseases?

Many cannot cross the blood-brain barrier. Overview / Efficacy 14

What property allows certain chemotherapeutic agents (e.g., nitrosoureas like carmustine) to cross the blood-brain barrier?

Being fat-soluble (lipophilic). Overview / Efficacy 15

Name two common gastrointestinal adverse effects of chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV), chemotherapy-induced diarrhea, mucositis, constipation, intestinal perforation. Overview / Adverse Eff. 16

What is mucositis, a common chemotherapy side effect?

Soft tissue erythema of buccal mucosa, gingival bleeding, multiple shallow ulcerations, and dysphagia. Overview / Adverse Eff. 17

What is the most common hematologic adverse effect of chemotherapy?

Myelosuppression, leading to granulocytopenia/lymphocytopenia (infection risk), thrombocytopenia (bleeding risk), and anemia (fatigue). Overview / Adverse Eff. 18

Name two common skin/hair adverse effects of chemotherapy.

Hair loss (alopecia), skin reactions (rashes, etc.). Overview / Adverse Eff. 19

What CNS side effect is associated with delayed emesis after chemotherapy and mediated by substance P/neurokinin-1 receptors?

Centrally induced vomiting. Overview / Adverse Eff. 20

What neurological side effect presents with pain, tingling, and sensory loss in a "stocking-glove" pattern?

Chemotherapy-induced peripheral neuropathy. Overview / Adverse Eff. 21

Name one class of chemotherapy agents commonly causing peripheral neuropathy.

Platinum-based agents (cisplatin), Taxanes (paclitaxel), or Vinca alkaloids (vincristine). Overview / Adverse Eff. 22

What potential adverse effect can chemotherapy have on sexual organs/fertility?

Gonadal damage leading to temporary azoospermia, premature ovarian failure, and infertility. (Esp. alkylating agents). Overview / Adverse Eff. 23

What is the mechanism of action of Antimetabolites?

Interfere with the synthesis of nucleic acids (DNA/RNA) by acting as analogs of normal metabolites (e.g., folate, pyrimidines, purines). Antimetabolites / MoA 24

What is the mechanism of action of Methotrexate (an antifolate)?

Competitively inhibits dihydrofolate reductase (DHFR), decreasing tetrahydrofolate needed for purine and dTMP synthesis. Antimetabolites / MoA 25

Name two major adverse effects of Methotrexate.

Myelosuppression, hepatotoxicity, pulmonary fibrosis, nephrotoxicity, mucositis, megaloblastic anemia, teratogenicity. Antimetabolites / AdvE 26

What is the mechanism of action of 5-Fluorouracil (5-FU) (a pyrimidine antagonist)?

Active metabolite 5-FdUMP forms a complex with thymidylate synthase, inhibiting dTMP production and thus DNA synthesis. Also incorporates into DNA/RNA. Antimetabolites / MoA 27

What specific adverse effect is associated with 5-Fluorouracil (5-FU)?

Palmar-plantar erythrodysesthesia (hand-foot syndrome). (Also myelosuppression, cardiotoxicity, GI toxicity). Antimetabolites / AdvE 28

What is the mechanism of action of Cytarabine (ara-C) (a pyrimidine antagonist)?

Pyrimidine analog incorporates into DNA, terminating the chain and inhibiting DNA polymerase. Antimetabolites / MoA 29

What specific adverse effect is associated with Cytarabine?

Cerebellar toxicity (neurotoxicity). (Also myelosuppression, megaloblastic anemia, hepatotoxicity, pancreatitis). Antimetabolites / AdvE 30

What is the mechanism of action of 6-Mercaptopurine (6-MP) (a purine antagonist)?

Converted to active metabolite by HGPRT, decreases de novo purine synthesis; incorporates into DNA as thiol analog, decreasing DNA synthesis. Antimetabolites / MoA 31

What enzyme metabolizes 6-Mercaptopurine (6-MP), leading to increased toxicity with inhibitors like allopurinol?

Xanthine oxidase. Antimetabolites / AdvE 32

What is the mechanism of action of Hydroxyurea (a ribonucleotide reductase inhibitor)?

Inhibits ribonucleotide reductase, decreasing DNA replication (S phase specific), leading to massive cytoreduction. Antimetabolites / MoA 33

What hematologic condition is Hydroxyurea used to treat by increasing HbF production?

Sickle cell disease (for crisis prophylaxis). Antimetabolites / Indic 34

What is the general mechanism of action of Alkylating Agents?

Covalently bind alkyl groups to DNA (especially guanine N-7), causing cross-links and strand breaks, inhibiting DNA replication. (Cell cycle-nonspecific). Alkylating Agents / MoA 35

What toxic metabolite of cyclophosphamide and ifosfamide causes bladder toxicity?

Acrolein. Alkylating Agents / AdvE 36

What specific bladder toxicities can cyclophosphamide/ifosfamide cause?

Hemorrhagic cystitis and bladder carcinoma. Alkylating Agents / AdvE 37

Which subgroup of alkylating agents can cross the blood-brain barrier due to high lipophilicity?

Nitrosoureas (e.g., carmustine, lomustine). Alkylating Agents / MoA 38

What specific toxicity is associated with Busulfan (an alkyl sulfonate)?

Severe myelosuppression ("busulfan lung" - pulmonary fibrosis, hyperpigmentation also common). Alkylating Agents / AdvE 39

What interaction can occur with Procarbazine (a hydrazine derivative)?

Disulfiram-like reaction with alcohol; Tyramine crisis (weak MAO inhibitor). Alkylating Agents / AdvE 40

What is the mechanism of action of Platinum-Based Agents (e.g., cisplatin, carboplatin, oxaliplatin)?

Form cross-links between DNA strands, inhibiting DNA replication. (Often grouped with alkylating agents). Alkylating Agents / MoA 41

Name two major toxicities associated with Cisplatin.

Nephrotoxicity (potentially Fanconi syndrome), Neurotoxicity (peripheral neuropathy), Ototoxicity, severe CINV. Alkylating Agents / AdvE 42

What is the mechanism of action of Topoisomerase I inhibitors (e.g., irinotecan, topotecan)?

Inhibit topoisomerase I, preventing DNA unwinding and causing single-strand breaks, leading to decreased replication and DNA degradation. (S/G2 phase specific). Topo Inhibitors / MoA 43

What specific adverse effect is characteristic of Irinotecan?

Severe diarrhea (cholinergic syndrome). (Also myelosuppression). Topo Inhibitors / AdvE 44

What is the mechanism of action of Topoisomerase II inhibitors (e.g., etoposide, teniposide)?

Inhibit topoisomerase II, causing double-strand DNA breaks and preventing replication. (Cell cycle arrest in S and G2 phase). Topo Inhibitors / MoA 45

Name one major adverse effect of Etoposide.

Myelosuppression, alopecia, hypotension. Topo Inhibitors / AdvE 46

What is the mechanism of action of Vinca Alkaloids (e.g., vincristine, vinblastine)?

Bind β-tubulin, inhibiting its polymerization into microtubules, thus preventing mitotic spindle formation and causing M-phase arrest. Mitotic Inhibitors / MoA 47

What is the dose-limiting toxicity typically associated with Vincristine?

Neurotoxicity (areflexia, peripheral neuropathy, paralytic ileus). ("Vincristine crisps the nerves"). Mitotic Inhibitors / AdvE 48

What is the dose-limiting toxicity typically associated with Vinblastine?

Myelosuppression ("Vinblastine blasts the bone marrow"). Mitotic Inhibitors / AdvE 49

What is the mechanism of action of Taxanes (e.g., paclitaxel, docetaxel)?

Hyperstabilize polymerized microtubules, preventing mitotic spindle breakdown and causing M-phase arrest. ("Tax rates are stable"). Mitotic Inhibitors / MoA 50

Name two major adverse effects of Taxanes.

Myelosuppression, neuropathy, hypersensitivity reactions. Mitotic Inhibitors / AdvE 51

What is the mechanism of action of Bleomycin (an antitumor antibiotic)?

Induces free radical formation, causing DNA strand breakage. (Cell cycle arrest at G2/M phase). Antibiotics / MoA 52

What is the major dose-limiting toxicity of Bleomycin?

Pulmonary fibrosis ("Bleomycin blocks your breath"). (Minimal myelosuppression). Antibiotics / AdvE 53

What is the mechanism of action of Anthracyclines (e.g., doxorubicin, daunorubicin)?

Inhibit topoisomerase II, intercalate into DNA, and generate free radicals, causing DNA breaks and inhibiting replication/transcription. (Cell cycle-nonspecific). Antibiotics / MoA 54

What is the major dose-limiting toxicity of Anthracyclines?

Cardiotoxicity (dilated cardiomyopathy with systolic CHF), which is dose-dependent. Antibiotics / AdvE 55

What is the mechanism of action of Protein Kinase Inhibitors (e.g., TKIs like imatinib)?

Inhibit specific protein kinases (often tyrosine kinases like BCR-ABL, c-KIT, EGFR, VEGFR, ALK, BRAF) involved in cell signaling, proliferation, and survival. (Variable cell cycle specificity). Kinase Inhibitors / MoA 56

What is the target of Imatinib?

BCR-ABL tyrosine kinase (in CML, Ph+ ALL) and c-KIT tyrosine kinase (in GIST). Kinase Inhibitors 57

What class of kinase inhibitors includes erlotinib and gefitinib?

EGFR tyrosine kinase inhibitors (used in NSCLC, pancreatic cancer). Kinase Inhibitors 58

What class of kinase inhibitors includes dabrafenib and vemurafenib?

V600E mutated-BRAF oncogene inhibitors (used in metastatic melanoma, NSCLC, thyroid cancer). Kinase Inhibitors 59

What mnemonic helps remember BRAF inhibitors?

VemuRAFenib and daBRAFenib are BRAF inhibitors. Kinase Inhibitors 60

What class of kinase inhibitors includes ibrutinib?

Bruton tyrosine kinase (BTK) inhibitors (used in CLL, mantle cell lymphoma, Waldenstrom). Kinase Inhibitors 61

What class of kinase inhibitors includes ruxolitinib?

Janus kinase (JAK) inhibitors (JAK1/JAK2; used in polycythemia vera, myelofibrosis). Kinase Inhibitors 62

What class of kinase inhibitors includes palbociclib?

CDK inhibitors (CDK4/6; used in metastatic breast cancer). Kinase Inhibitors 63

What is the mechanism of action of L-asparaginase?

Enzyme that cleaves L-asparagine, depleting the source needed by leukemic cells (cytotoxicity specific to leukemic cells, typically ALL). (G1 phase specific). Others / Enzymes 64

What is the mechanism of action of Proteasome Inhibitors (e.g., bortezomib)?

Inhibit proteasome degradation of ubiquitinated proteins (like p53), leading to accumulation, G2/M arrest, and apoptosis. Others / Proteasome 65

What is the mechanism of action of PARP Inhibitors (e.g., olaparib)?

Inhibit poly (ADP-ribose) polymerase, decreasing repair of single-strand DNA breaks (effective in BRCA-mutated cancers). (G2/S phase specific). Others / PARP 66

What detoxifying agent is given after high-dose Methotrexate, and why?

Leucovorin (folinic acid), a precursor of tetrahydrofolate, to rescue normal cells from folate depletion ("Leucovorin rescue"). Detoxifying Agents 67

What detoxifying agent is given with cyclophosphamide or ifosfamide, and why?

Mesna (2-Mercaptoethane Sulfonate Na) and fluids; mesna binds the toxic metabolite acrolein, preventing hemorrhagic cystitis. Detoxifying Agents 68

What interventions can help prevent Cisplatin nephrotoxicity?

Amifostine (free radical scavenger) and IV saline hydration (chloride diuresis). Detoxifying Agents 69

What detoxifying agent can help prevent Anthracycline cardiotoxicity?

Dexrazoxane (iron chelating agent). Detoxifying Agents 70