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STEP Pharm I > Cancer III > Flashcards

Cancer III Flashcards

1
Q

What are vinca alkaloids derived from?

A

The vinca alkaloid class of naturally occurring cancer chemotherapy agents are extracted from the periwinkle plant.

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2
Q

How do vinca alkaloids work at a basic level? Are they cell-cycle specific?

A

The vincas block tubulin polymerization; based upon this mechanism, it is entirely predictable that one of the mechanisms of resistance specific to these drugs is mutation in the beta-tubulin structure, reducing the drug affinity for the target. M phase specific

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3
Q

Resistance to vinca alkaloids?

A

increased drug efflux from the tumor cell by active pump proteins- e.g. multi-drug resistance protein (MRP), breast cancer resistance protein (BCRP), or P-gp.

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4
Q

How are vinca alkaloids administered?

A

IV

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5
Q

How are vinca alkaloids eliminated?

A

hepatic

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6
Q

Side effects of vinca alkaloids?

A

leukopenia with vinblastine, not vincristine, Vincristine- neurotoxic symptoms alopecia, peripheral neuropathy in both

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7
Q

What are the taxane drug members?

A

Paclitaxel and Docataxel- both are synthetic antineoplastic agents

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8
Q

How are taxane drugs different from vinca alkaloids?

A

These drugs inhibit disassembly of the microtubules, in contrast to the vincas, which prevent the assembly of this critical nuclear component.Also M phase specific

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9
Q

How are taxanes administered?

A

IV

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10
Q

What must paclitaxel (taxol) be administered with?

A

a surfactant, cremaphor

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11
Q

What must docataxel (taxotere) be administered with?

A

a surfactant, polysorbate 80

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12
Q

Why must both taxes be given with surfactants?

A

they are both relatively insoluble

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13
Q

What are the side effects of Palitaxel?

A

peripheral neuropathy, hypersensitivity infusion reactions

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14
Q

What are the side effects of Docataxel?

A

very low WBC counts, edema-fluid retention, peripheral neuropathy,

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15
Q

Where do vinca alkaloids bind to growing microtubules? Why?

A

Vinca alkaloids bind preferentially with the + end of the microtubules and therefore inhibit the addition of new tubulin subunits to the microtubule.

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16
Q

Where do taxanes bind to growing microtubules? Why?

A

Taxanes bind to a site on the beta subunit and stabilize the interactions between the tubulin subunits. With taxanes, the nucleus essentially becomes filled with microtubules.

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17
Q

Are taxanes and vinca alkaloids cell cycle specific?

A

Yes, both the vinca alkaloids and the taxanes are cell cycle specific drugs since the microtubules only become critical to nuclear events during the M phase of the cell cycle.

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18
Q

Which anticancer drugs are most commonly associated with neurotoxicity?

A

vincas, taxanes, and platinum drugs, especially cisplatin

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19
Q

What parts of neurons do taxanes and vinca alkaloids target?

A

distal axons (which rely upon microtubules to transport nutrients along the length of the axon)

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20
Q

How do platinum drugs target neural cells?

A

they accumulate in the ganglion cells where apoptosis ensues via oxidative stress

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21
Q

Describe the neuropathies associated with anticancer drugs as described above?

A

these neuropathies are seen as: paresthesias in a stocking-glove distribution (pins and needles), areflexia (no reflexes), loss of proprioception, and vibratory sensation and loss of taste

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22
Q

Patients receiving these classes of drugs should receive evaluation of peripheral nerve function as a routine. There is no easy correlation between accumulated dose and toxicity. Once treatment is completed, some or all of the lost function may return, but not always. It varies by drug, drug history and the individual patient.

A

Patients receiving these classes of drugs should receive evaluation of peripheral nerve function as a routine. There is no easy correlation between accumulated dose and toxicity. Once treatment is completed, some or all of the lost function may return, but not always. It varies by drug, drug history and the individual patient.

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23
Q

What are the Camptothecins?

A

irinotecan and its metabolite SN-38 and topotecan

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24
Q

How do Camptothecins work?

A

work by inhibiting topoisomerase I by preventing reformation after single strand breaks to relieve torsion

25
Q

Are Camptothecins cytotoxic alone?

A

No, this activity is not sufficient to cause cytotoxicity because the complexes are easily reversible once the drug is removed.

26
Q

What is required for Camptothecins to be cytotoxic?

A

Ongoing DNA synthesis is required to cause lethal cellular damage. Irreversible DNA damage occurs when a DNA replication fork encounters the irinotecan or SN-38/topoisomerase I complexes resulting in double-strand DNA breaks (Fork Collision Model).

27
Q

When are Campothecins active in the cell cycle?

A

Camptothecins are highly S-phase specific in their activity due the requirement of DNA synthesis. This is in contrast to the topo II inhibitors, which are considered cell cycle non-specific drugs.

28
Q

How are irinotecan and topotecan administered?

A

IV

29
Q

Which Campothecin has a longer half-life?

A

Irinotecan.

30
Q

Irinotecan is metabolism via phase II glucuronidation in the liver. What is the significance in terms of potential toxicity (coupled with its extended half life)?

A

Polymorphisms in glucuronosyltransferase (UGT) activity means that some patients experience higher toxicity to a given drug dose because of diminished capacity to excrete the drug.

31
Q

What is Gilbert’s syndrome?

A

a functional promoter SNP of the UGT (think phase II metabolism) 1A1 gene and that could represent a pharmacogenetic risk factor for irinotecan toxicity, (but study data remain controversial.)

32
Q

As stated, Irinotecan is metabolized in the liver. How is Topotecan eliminated?

A

Renal. Thus, dose adjustment necessary in renal disfunction

33
Q

How are the toxicities of Irinotecan and Topotecan different?

A

Irinotecan produces diarrhea as the dose-limiting toxicity

34
Q

Similar toxicities of Irinotecan and Topotecan?

A

elevated liver enzymes, immunosuppression

35
Q

What is Etoposide?

A

a semisynthetic drug that is an orally active topoisomerase II inhibitor. given PO.Only side effects are myelosuppression and alopecia

36
Q

How is Etoposide eliminated?

A

renal

37
Q

What are Anthracyclines derived from?

A

soil mold, Strepomyces.

38
Q

What are the members of Anthracyclines?

A

Doxorubicin and Daunorubicin

39
Q

What is Doxorubicin commonly used to treat?

A

Doxorubicin is more active in solid tumors such as breast cancer than daunorubicin. Doxorubicin is not commonly used in the treatment of acute myelogenous leukemia due to the increased incidence of mucositis and cardiotoxicity as compared to daunorubicin or idarubicin.

40
Q

What are some of the mechanisms of action of Anthracyclines?

A

1) Being linear structures they can intercalate between the two stands of DNA, thus altering the critical topology. 2)They can also bind to and stabilize the DNA-topoisomerase II complex, and, 3) they can generate free radicals

41
Q

What are some mechanisms of resistance against Anthracyclines?

A

active pump processes, mutation or changes in the expression of topoisomerase, or increased glutathione peroxidase expression, which produces increased ability for the cell to “soak up” free radical generated by drug treatment.

42
Q

What are some side effects of Anthracyclines?

A

cardiotoxicity, which includes initial electrocardiographic abnormalities (with the possibility of arrhythmias) and slowly developing cardiomyopathy and congestive heart failureNOTE: Doxorubicin is red colored so red urine is very common and doesn’t indicate any side-effect.

43
Q

How can you protect against cardiomyopathy in Anthracycline patients? 2 ways

A

Dexrazoxane, an inhibitor of iron-mediated free radical generation, may protect against cardiotoxicity. Liposomal formulations of doxorubicin may also be less cardiotoxic.

44
Q

What is Bleomycin? How does it work? Is it cell cycle specific?

A

A mixture of glycopeptides isolated from a culture broth of the mold Streptomyces. G2 cell specific The drug binds to DNA, causes single and double strand breaks, inhibiting protein synthesis in G2.

45
Q

How is Bleomycin given?

A

IV/IM. It is inactivated by tissue enzymes but some renal clearance of drug also occurs. Increased capacity for inactivation is one of the mechanisms of drug resistance to this compound.

46
Q

Common toxicities of Bleomycin?

A

pulmonary fibrosis, which develops slowly and is dose-limiting. Hypersensitivity reactions (chills, fever, anaphylaxis) are common, as are mucosal cutaneous reaction (alopecia, blister formation, hyperkeratosis).

47
Q

What is Asparaginase?

A

an enzyme product that degrades asparagine, thus ‘starving” protein synthesis from this essential component.

48
Q

How can the half-life of Asparaginase be extended?

A

A pegylated conjugate-product is available that tends to extend the duration of drug persistence and therefore activity in the body.

49
Q

What are the side effects of Asparaginase?

A

pancreatitis and hyperglycemia

50
Q

What is Lenazidoamide? How does it work? 4 things

A

derive of thalidomide that:1) inhibits tumor cell proliferation, 2) inhibits tumor adhesion to stroma, 3) inhibits angiogenesis, and 4) enhances NK cell activity

51
Q

Side effects of Lenazidoamide?

A

blood dyscrasia, peripheral sensory neuropathy, embolism

52
Q

What is Lenazidoamide commonly used to treat?

A

multiple myeloma and myelodysplastic syndrome

53
Q

What is all-trans-retinoic acid (Tretinoin)? What is used to treat?

A

A retinoid drug that acts upon transcriptional regulation in the nucleus. In acute promyelocytic leukemia (APML), a balanced (15;17) chromosomal translocation creates a chimeric gene that drives the expression of a fusion protein consisting of a portion of the promyelocytic leukemia protein (PML) and RARα.

54
Q

What does the PML-RARa fusion protein do?

A

The PML-RARα fusion protein retains the capacity to bind to promoter gene retinoic acid response elements (RAREs) (which normally regulate myeloid differentiation) but has a much higher affinity for co-repressors than normal RXR-RARα heterodimers. As a result, physiologic levels of retinoic acid fail to activate gene transcription, resulting in a block in differentiation of myeloids that contributes to the immature phenotype of APML. NOTE: Normally retinoic acid binding releases co-repressors and initiates myeloid gene transcription

55
Q

How can the blockade of differentiation be overcome?

A

by pharmacologic doses of all-trans retinoic acid (ATRA), which is capable of binding to the PML-RARα fusion protein and displacing co-repressors.

56
Q

Large doses of retinoids are associated with what?

A

a condition known as retinoic acid syndrome which is characterized by fever, weight gain, and pleural or pericardial effusions

57
Q

What are some of the side effects of Tretinoin?

A

dry skin, cheilitis (lip inflammation), hyperlipidemia

58
Q

T or F. Anticancer drugs are seldom used as single agents but rather as part of combinations which are often referred to by an acronym

A

T. RULES: As a rule, no two drugs in a given regimen act through the same mechanism; this helps to avoid the problem of cross-resistance. Also, drugs with overlapping toxicities are to be avoided because that would necessitate dose reduction, the antithesis of effective chemotherapy. Each drug in a regimen has proven activity against the type of tumor for which it is being employed.

STEP Pharm I (36 decks)

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