Pharm: Anticancer Drugs 3 Flashcards
List the two drug classes that act by blocking microtubule activity in the nucleus.
vinca alkaloids= vincristine & vinblastine
taxanes= docetaxel & paclitaxel
Vinca alkaloids block:
Cancers can overcome this MOA by:
tubulin polymerization
Overcome by mutation in the beta-tubulin structure, reducing drug affinity for target
What are universal resistance mechanisms to vinca alkaloids?
increased drug efflux (multi-drug resistance protein MRP or breast cancer resistance protein BCRP)
What phase of the cell cycle to vinca alkaloids halt the tumor cell in?
Metaphase> results in apoptosis
Describe the toxicities of the vinca alkaloids.
Leukopenia with vinblastine, NOT vincristine
Alopecia and local cellulitis if extravasated
neurotoxic symptoms, more so in vincristine
Extravasational necrosis
High-dose vincristine causes severe constipation
Although both vinca alkaloids and taxanes inhibit microtubule function, taxanes work differently than vincas. Explain how.
Taxanes inhibit disassembly of the microtubules, in contrast to vincas, which prevent assembly.
Describe the side effects of the taxanes.
Paclitaxel:
Bone marrow suppression
High incidence of peripheral neuropathy
Hypersensitivity infusion rxns
Docetaxel:
Peripheral neuropathy
More severe, but short-lived neutropenia
List the 3 classes of anticancer drugs most commonly associated with neurotoxicity.
Microtubule blockers: vinca alkaloids & taxanes
Alkylating agent: Cisplatin
Vinca alkaloids and taxane drugs will cause peripheral neuropathy because:
They inhibit microtubules that are necessary for transport of signaling molecules to terminal ends of an axon.
Whereas the vincas and taxanes affect the distal axons of the nerves, alkylating agents such as Cisplatin will produce their toxicity by:
accumulating in the ganglion cells where apoptosis ensues
Describe the character of the neuropathies caused by the vinca alkaloids, taxanes, and the alkylating agent Cisplatin.
Neuropathies seen as paresthesias in a stocking-glove distribution, areflexia, loss of proprioception, vibratory sensation, and loss of taste
___________ (drug) is associated, especially, with a “glove and stocking” neuropathy characterized by tingling that originates in the tips of the hands and soles of the feet, sharply stopping at the wrists and ankles.
Paclitaxel (a taxane)
This enzyme cuts both strands of the DNA helix in order to manage DNA tangles and supercoils. This is essential for strand separation and DNA replication.
Topoisomerase II
Are the drugs that inhibit the action of topoisomerase II cell cycle specific?
No
What is the class of drugs that blocks Topo II function?
Camptothecins
How can tumor cells overcome the action of the Camptothecins?
Efflux mechs, alter the drug target (topo II)
Name the two Camptothecin drugs.
Irinotecan & Topotecan
The camptothecins are specific for which phase of the cell cycle?
They are not cell cycle specific, remember?! They’re Topo II inhibitors!
Gilbert’s syndrome is associated with increased toxicity of which camptothecin drug?
irinotecan
The camptothecins are associated with what toxicities?
Topotecan:
myelosuppression, musositis & diarrhea, elevated hepatic enzymes
Irinotecan:
dose limiting diarrhea, myelosuppression, N/V, mucositis, alopecia, elevated hepatic enzymes
Describe the MOA of etopside.
Topoisomerase II inhibitor
Describe the side effects of etopside.
Typical of chemo drugs: alopecia, myelosuppression
Describe the MOA of the Anthracycline class of anticancer drugs.
Intercalate with DNA, altering critical topography.
Free radical formation
Topo II stabilization, inhibiting DNA replication
Describe how the increased glutathione peroxidase expression by cancers can cause resistance to anthracyclines.
produces increased ability for the cell to “soak up” free radical generated by the drug treatment.
List the 3 anthracycline drugs.
Daunorubicin, Doxorubicin, Idarubicin
Describe the side effects of the anthracycline class of drugs.
Myelosuppression, alopecia, GI disturbances
Acute: tachycardia, arrhythmias, hypotension, reduced ejection fraction (tachycardia), troponin-T release
Chronic: CHF- 50% mortality
Cardiotoxicity= most distinctive ADE
How can you protect normal tissue from the ADEs of anthracyclines?
dexrazoxane, iron chelating agent (inhibits Fe free radical generation), may protect against cardiotoxicity
Liposomal Dox preps less cardiotoxic
Describe the MOA of Bleomycin
Causes single & double strand DNA breaks
Describe a mechanism of drug resistance tumor cells express towards bleomycin.
Increased capacity for inactivation, degradation by specific hydrolase
Describe the side effects of treatment with bleomycin.
pulmonary dysfunction (dose limiting)
Hypersensitivity rxns
alopecia, blisters, keratosis
(skin/lung tox. may be related to low levels of hydrolysis)
How does asparaginase (Pegaspargase) work as an anticancer drug?
degrades asparagine, thus ‘starving’ protein synthesis of this essential component.
What are the significant toxicities of pegaspargase?
pancreatitis, immune system suppression and problems in regulating blood sugar levels.
Describe the indications and specific actions of Lenalidomide.
Indications: myeloma and myelodyspastic syndrome
Uses: Inhibits tumor cell proliferation, inhibits tumor cell adhesion to stroma, inhibits angiogenesis, enhances NK cell activity
Describe the side effects of lenalidomide.
blood dyscrasias, peripheral sensory neuropathy, sedation, constipation, venous and atrial embolism
Describe the MOA of the retinoid class of anticancer drugs.
Overcome the block (by transcriptional co-repressors) in myeloid differentiation that contributes to acute promyelocytic leukemia (APML). Retinoic acid binds transcriptional co-activators resulting in proper gene expression and granulocytic differentiation.
As a reminder:
Allopurinol and rasburicase are given as adjuvants to mitigate the effects of:
Tumor lysis syndrome
- reduce uric acid level; renal protective
As a reminder:
Mesna is given as an adjuvant to mitigate the negative effects of:
Cyclophosphamide, ifosfamide
- protect against acrolein product
As a reminder:
Amifostine is given as an adjuvant with:
Cisplatin
- cytoprotection
As a reminder:
Leucovorin is given as an adjuvant with:
MTX- metabolic rescue
5-FU- enhanced action
As a reminder:
Allopurinol is given as an adjuvant with:
6-MP (mercaptopurine)
- CAUTION: increases toxicity!
As a reminder:
Dexroxazone is given as an adjuvant with:
Anthracyclines
- Fe chelator; reduces cardiotoxicity
Neurotoxicity is especially associated with which anticancer drug?
Vincristine
Leukopenia and lesser peripheral neurotoxicity are associated with which vinca alkaloid?
Vinblastine
GI toxicity, avoidance of Gilbert syndrome, and AchE inhibition are associated with which camptothecin?
irinotecan
Peripheral neuropathy is especially associated with which taxane?
Paclitaxel
Edema-fluid retention and peripheral neuropathy are associated ADEs with which taxane?
Docataxel
Cardiotoxicity is especially associated with which class of anticancer drugs?
Anthracyclines
Pulmonary fibrosis is especially associated with which anticancer drug?
Bleomycin
Pancreatitis is especially associated with which anticancer drug?
Asparaginase (Pegaspargase)
