Anticancer Drugs: Topoisomerase and Spindle Inhibitors Flashcards
1
Q
While we do not need to know which drugs are used to treat which tumors at this point, why is it important to note, for example, that there is a difference in the tumors treated with Vincristine and Vinblastine?
A
- Mechanistically comparable drugs, like docetaxel and paclitaxel, or vincristine & vinblastine, show differences in clinical utility
- Even within a drug class, for example the anthracyclines
(doxorubicin and daunorubicin), the presence or absence of as little as a terminal hydroxyl function can play a
significant role in the spectrum of antitumor activity
2
Q
What are the MOA and MOR of the VINCA ALKALOIDS?
A
- Naturally occuring cancer chemotherapy agents extracted from periwinkle plant (vincristine, vinblastine)
- MOA: block alpha-beta tubulin polymerization by binding to beta tubulin (preferentially, the + end), causing metaphase arrest and apoptosis
- MOR: mutation in the beta-tubulin structure, reducing drug affinity for target; universal MORs incl. increased drug efflux via active pump proteins (aka, multi-drug resistance protein, MRP, breast cancer resistance protein, BCRP, or P-glycoprotein)
- NOTE: cell cycle specific (only M phase)
3
Q
How are the VINCA ALKALOIDS administered and eliminated? What are the associated toxicities?
A
- IV admin; hepatic elim
-
Toxicity: myelosuppression
1. Leukopenia with vinblastine, NOT vincristine
2. Hair loss and local cellulitis if extravasated
3. May cause neurotoxic symptoms
4. Extravasational necrosis -
Vincristine only toxicity:
1. More pronounced cumulative neurotoxic effects
2. Inadvertent ITH admin produces fatal central nuerotoxicity, w/seizures and irreversible coma
3. High dose causes severe constipation
4
Q
What are the MOA and MOR of the TAXANES?
A
- Docataxel: semi-synthetic, non-toxic European Yew tree extract
- Paclitaxel: semi-synthetic from Pacific Yew tree
- MOA: binds to beta-tubulin, stabilizing interactions b/t tubulin subunits, inhibiting disassembly of microtubules; nucleus essentially becomes filled with microtubules
- MOR: efflux, target mutation
- Both IV, but relatively insoluble, so must be admin w/surfactant, which can affect pK of solubilized drug
1. Cremaphor w/Pac; polysorbate 80 w/Doca - NOTE: cell cycle specific (only M phase)
5
Q
What are the TAXANE toxicities?
A
- Extensive CYP metabolism
- Both: peripheral neuropathy (high w/Pac), blood dyscrasias (diseases)
- Paclitaxel: bone marrow suppression, hypersensitivity infusion reactions (prophylactic antihistamines and steroids)
- Docetaxel (>potency): more severe, but short-lived, neutropenia, lower incidence of hypersensitivity
6
Q
Describe the neurotoxicity of anticancer drugs, and provide examples.
A
- Cumulative and sometimes irreversible toxicity
- Vincas/taxanes affect distal nerve axons, which rely on microtubules to transport nutrients along axon
- Platinum drugs accumulate in ganglion cells, and damage or oxidative stress = apoptosis
- Peripheral neuropathy: paresthesias in stocking-glove distribution, areflexia (reflex loss), loss of proprioception and vibratory sensation, and loss of taste
7
Q
What is stocking-glove neuropathy?
A
- Pts report tingling that originates in fingertips and toes, progressing to palms and soles, and stopping abruptly at wrists and ankles
- Dose reductions and chemo mods required to prevent progression and attempt to reverse neuropathy (onset doesn’t seem 2 correlate w/specific or cumulative dose)
- No easy correlation b/t accumulated dose and toxicity; once tx completed, some or all lost function may return, but not always
- Routine evaluation of peripheral nerve function with vinca alkaloids, taxanes, and platinum drugs
8
Q
What is the MOA of the CAMPTOTHECINS?
A
- Stabilize DNA-topoisomerase I cleavable complex: ss and dsDNA breaks
- Water-soluble derivatives of camptothecin (CPT), a cytotoxic plant alkaloid isolated from the Chinese tree Camptotheca acuminata (happy tree, cancer tree, or tree of life)
- Cell-cycle non-specific
- Topoisomerase I: energy-dependent enzyme that cuts one of two strands of DNA, relaxes, and reanneals
- C20: CH2CH3, OH, ring conformation essential for activity
9
Q
What are the MOR to the CAMPTOTHECINS?
A
- G2 arrest correlates w/descreased drug sensitivity
- In vitro: increased efflux (P-gp, MRP, BCRP), mutation or decreased expression of target, Topo I
10
Q
What are the toxicities of IRINOTECAN and TOPOTECAN?
A
- Both IV; 1/2 life of Irinotecan > Topotecan
-
Irinotecan: hepatic metabolism
1. UGT phase II metabolism polymorphisms impact clinical use: DEC conjugation = INC neutropenia (severe toxicity in pts w/Gilbert syndrome due to SNP in UDP-glucuronosyltransferase 1A1 gene)
2. Dose-limiting diarrhea: >24hr, Loperamidine effective except in severe cases (generally resolves in week; rarely fatal)
3. <24hr AchE inhibition responsive to atropine (helps stabilize heart b/c AchE inhibition causes hyperstimulated PARA b/c no ACTH breakdown)
4. Myelosuppression: anemia, leukopenia, neutropenia
5. N/V, mucositis, allopecia
6. Elevation in hepatic enzymes -
Topotecan: renal elimination; dose adjustment
1. Neutropenia, +/- thrombocytopenia
2. Mucositis and diarrhea, N/V, elevated hepatic enzymes
11
Q
What are the MOA, MOR, and toxicities for ETOPOSIDE?
A
- Semisynthetic drug from resin of mandrake root
- MOA: forms complex with topo-II and DNA
- Oral admin, renal elim
- MOR: INC efflux; mutated or DEC topo II expression
- Toxicity: myelosuppression and allopecia
12
Q
What are the MOA and MOR of the ANTHRACYCLINS?
A
- Dox and Dauno originally isolated from soil mold, Streptomyces (subsequent agents semi-synthetic)
- Multiple MOA:
1. Intercalate with DNA b/c linear structures, affecting transcription and replication
2. Complex with Topo II and DNA
3. Free radicals from semiquinone - MOR: INC efflux (P-gp, MRP, BCRP), INC glutathione peroxidase (elim free radicals), DEC topo II or mutation
- NOTE: Doxo (1 of most active chemo agents) more active in solid tumors (i.e., breast cancer), but not used to tx AML due to increased incidence of mucositis and cardiotoxicity compared to other anthracyclins
13
Q
What are the ANTHRACYCLIN toxicities?
A
- Myelosuppression, stomatitis, alopecia, GI disturbances, extravasational necrosis
-
Acute (reversible): tachycardia, arrhythmias, hypotension, DEC ejection fraction, troponin-T release
1. Initial electrocardiographic abnormalities and slowly developing cardiomyopathy and CHF -
Chronic (irreversible): CHF -> 50% mortality
1. MAX dose limits: 550 mg/m adult, 300 children
2. Protection w/Dexrazoxane iron-chelating agent (inhibitor of iron-mediated free radical generation)
3. Exacerbation with other cardiac damaging interventions - NOTE: liposomal Doxo preparations less cardiotoxic, and any systemic drug will produce red urine (not toxic)
14
Q
What are the MOA, MOR, and toxicities of BLEOMYCIN?
A
- Mixture of glycopeptides from culture broth of the mold Streptomyces -> parenteral (IV or IM) admin only
- Cell-cycle specific
- MOA: drug-Fe complex oxidizes deoxyribose of thymidilate and o/nucleotides -> ss and dsDNA breaks
- MOR: degradation by specific hydrolase (and some renal clearance) -> low activity in skin and lung; DEC uptake, INC repair, INC inactivation (thiols/thiol-rich proteins)
-
Toxicity: pulmonary (5-10%) -> dry cough, pneumonitis, and fibrosis (dose-limiting); 1 & 2 below are common
1. Hyperpigmentation, hyperkeratosis, erythema, ulceration, alopecia (mucocutaneous reactions)
2. Hypersensitivity rxns: chills, fever, anaphylaxis
3. Little myelosuppression
15
Q
What are the MOA, MOR, and toxicities of PEGASPARGASE?
A
- Pegylated asparaginase (modification extends duration of drug persistence and activity in the body)
- MOA: aspariginase enzyme degrades asparagine to aspartic acid + ammonia, starving protein synthesis of essential component
- MOR: upregulation of asparagin synthetase
- Toxicity: pancreatitis (necrotic, inflammatory), immune suppression, hyperglycemia (no insulin)
