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SBL > Cancer Pharm: Alkylating Agents > Flashcards

Cancer Pharm: Alkylating Agents Flashcards

1
Q

Major MOA of alkylating agents and causes arrest where in cell cycle?

A
  • Transfer of alkyl group to DNA –> DNA cross-linking
  • Arrest occurs in late G1, early S phase
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2
Q

What are 3 mechanisms to resistance of Alkylating agents?

A
  • ↑ capability to repair DNA lesion –> ↑ expression MGMT
  • ↓ cellular transport of the alkylating drug
  • ↑ expression of glutathione
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3
Q

What is the most widely used alkylating agent that has a high oral bioavailability and can be given IV?

A

Cyclophosphamide

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4
Q

Which intermediate of Cyclophosphamide is further broken down into products that have cytotoxic effects on tumor cells; what are these products?

A

Aldophosphamide —> Phosphoramide mustard + Acrolein

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5
Q

Which toxic metabolite of Cyclophosphamide is responsible for the antitumor effects?

A

Phosphoramide mustard

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6
Q

Which toxic metabolite of Cyclophosphamide is associated with hemorrhagic cystitis?

A

Acrolein

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7
Q

What should patients receive when on high doses of Cyclophosphamide?

A

Vigorous IV hydration

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8
Q

Complete remissions and presumed cures have been seen with Cyclophosphamide when given as a single agent for what type of cancer?

A

Burkitt Lymphoma

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9
Q

Which alkylating agent has been used topically for tx of cutaneous T-cell lymphoma; why has it been largely replaced?

A
  • Mechlorethamine
  • Most reactive drug in the class; more stable drugs exist
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10
Q

Which alkylating agent causes less N/V and alopecia compared to other drugs in this class; toxicity of this drug is mostly of what kind?

A
  • Melphalan
  • Toxicity is mostly hematological
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11
Q

Major dose-dependent AE of the alkylating agent, Chlorambucil?

A
  • Well tolerated in small daily doses
  • Large oral doses can cause N/V (>20mg)
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12
Q

What is the clinical use for the alkylating agent, Chlorambucil?

A
  • Chronic Lymphoblastic Leukemia

****ChLorambuciL (CLL)****

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13
Q

Which 2 alkylating agents are lipid soluble nitrosoureas allowing them to cross BBB and be effective in treating brain tumors?

A
  • Carmustine and Streptozocin
  • Generate both alkylating and carbamylating moieties
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14
Q

What is the major action of the alkylating nitrosourea, Carmustine; how can resistance develop?

A
  • Alkylation of DNA
  • This can be repaired by MGMT
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15
Q

What are the AE’s of the nitrosourea, Carmustine; which AE’s arise with high doses?

A
  • Profound and delayed myelosuppression: recovery 4-6 weeks after a single dose
  • High doses w/ bone marrow rescue, produces hepatic VOD, pulm. fibrosis, renal failure, and 2’ leukemia
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16
Q

What is the clinical use of Carmustine and what makes this drug so effective in these tumors?

A
  • Malignant Glimoas (implantable Carmustine wafer)
  • Methylation of the MGMT promter inhibits MGMT expression in 30% of primary gliomas
  • Assoc. w/ sensitivity to carmustine and other nitrosureas
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17
Q

The nitrosourea, Streptozocin, has a high affinity for what cells?

A

Cells of the islets of the Langerhans in the pancreas

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18
Q

What are some of the frequent and serious AE’s associated with Streptozocin?

A
  • Frequent nausea
  • Mild reversible renal or hepatic toxicity occurs in ~2/3 of cases
  • 10% will have cumulative dose renal toxicity CAN lead to renal failure
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19
Q

What are the 2 clinical uses of Streptozocin?

A
  • Human pancreatic islet cell carcinoma
  • Carcinoid tumors
20
Q

What is the Aziridine drug in the alkylating agent class and what is its MOA?

A
  • Thiotepa
  • Hepatic CYPs convert thiotepa to TEPA —> both thiotepa and TEPA form DNA cross links
21
Q

What are the unique AE’s of Thiotepa at high doses?

A

Mucosal and CNS toxicity + coma and seizure

22
Q

What is the clinical use of the aziridine, thiotepa?

A

For high-dose chemo regimens in transplants for hematological malignancies

23
Q

What are the AE’s associated with the alkylsulfonate, Busulfan, at high doses?

A

Pulmonary fibrosis** + GI mucosal damage + hepatic VOD

24
Q

Which anti-convulsants are given concomitantly with Busulfan to protect against acute CNS toxicities?

A

Non-enzyme inducing benzodiazepines —> Lorazepam and Clonazepam

25
Q

What are 4 known MOA of the alkylating agent, Procarbazine?

A
  • Converted by highly reactive alkylating species that methylate DNA
  • Produces chromosome damage thru chromatid breaks and translocations
  • Inhibits DNA, RNA, and protein biosynthesis
  • Prolongs interphase (cell cycle)
26
Q

Why does resistance to procarbazine develop rapidly when used as monotherapy?

A

Increased expression of MGMT

27
Q

Which alkylating agent has the highest carcinogenic potential?

A

Procarbazine

28
Q

What are 3 of the unique AE’s associated with Procarbazine?

A
  • ↑ risk secondary cancer: acute leukemia
  • Augments sedative effects: concomitant CNS suppressants should be avoided (i.e., alcohol)
  • Disulfiram-like actions: avoid alcohol
29
Q

What is the MOA of Dacarbazine; how can resistance develop?

A
  • Prodrug; functions as methylating agent after being convertedto metabolite MTIC
  • Resistance develops due to removal of methyl groups by MGMT
30
Q

What is the most common AE of the alkylating agent, Dacarbazine?

A

90% of pt’s experience N/V –> 1-3 hours after tx, can last 12 hours

31
Q

What is the MOA of the alkylating agent, Bendamustine?

A
  • Forms cross-links w/ DNA = single and double strand breaks
  • Inhibits mitotic checkpoints and induces mitotic catastrophe
32
Q

If there is resistance to alkylating agents, what is a non-classical alkylating agent which can be used?

A

Bendamustine; only partial cross-resistance w/ other alkylating agents

33
Q

What are 3 AE’s of Bendamustine and which are rapidly reversible?

A
  • Myelosuppression and Mucositis (rapidly reversible)
  • Mild N/V
34
Q

What are the known MOA for the alkylating agents that are platinum analogs; work during what stages of cell cycle?

A
  • Kill tumors cells in ALL stages of the cell cycle
  • Binds DNA through the formation of intra- and inter-strand cross-links
  • Inhibits DNA synthesis and function
35
Q

The alkylating agents, which are platinum analogs have synergism with which 3 other classes?

A

Other alkylating agents + fluoropyrimidine + taxanes

36
Q

Which precautions are taken with Cisplatin to prevent renal toxicity?

A
  • A chloride diuresis is established by infusion of 1-2 L normal saline prior to tx to prevent renal toxicity
  • Vigourous IV hydration required
37
Q

Which metal can inactivate Cisplatin and how does this affect the administration of the drug?

A
  • Aluminum
  • Drug should not come in contact w/ needles or other infusion equipment containing aluminum
38
Q

After administration which 4 areas contain high levels of Cisplatin?

A

Kidney, liver, intestine, and testes

39
Q

What are 5 AE’s of Cisplatin and how are they controlled?

A
  • Nephrotoxicity - pre-tx w/ hydration and chloride diuresis
  • Ototoxicity = tinnitus and high-frequency hearing loss
  • Almost ALL have N/V - controlled w/ 5HT3 receptor agonists, NK1 receptor antagonists and high-dose steroids
  • Electrolyte disturbances = common; tubular damage may lead to renal electrolyte wasting and produce tetany if left untreated
  • Anaphylactic-like rxns occurring minutes after administration
40
Q

What are some AE’s associated with high doses/multiple cycles of Cisplatin?

A
  • Progressive peripheral motor and sensory neuropathy (may worsen after stopping drug)
  • Mild to moderate myelosuppression —> anemia
  • Can lead to development of AML –> usually 4 years+ after tx
41
Q

How does the administration of Carboplatin differ from Cisplatin?

A
  • Given via IV (like cisplatin)
  • BUT vigorous IV hydration is NOT required
42
Q

What is a unique AE associated with the platinum analog, Carboplatin, and how does it compare to Cisplatin?

A
  • WELL tolerated clinically; less nausea, neurotoxicity, ototoxicity, and nephrotoxcity (compared to cisplatin)
  • Hypersensitivity rxn: graded doses of drug and more prolonged infusion leads to desensitization
  • Myelosuppression = common
43
Q

Carboplatin can be an effective alternative to Cisplatin in which patients?

A

Pt’s w/ impaired renal function (adjust dose), refractory nausea, significant hearing impairment, and neuropathy

44
Q

What is the dose-limited toxicity for Carboplatin vs. Oxaliplatin?

A
  • Carboplatin = myelosuppression —> thrombocytopenia
  • Oxalipatin = neurotoxicity —> peripheral sensory neuropathy
45
Q

What is the acute vs. cumulative dose form of the peripheral sensory neuropahty which may be seen with Oxaliplatin tx?

A
  • Acute = often triggered by exposure to cold liquids; paresthesias or dyesthesias in the UE’s and LE’s, mouth, and throat
  • Cumulative = similar to cisplatin neurotoxicity; dysesthesias, ataxia, numbness of extremities
46
Q

Other than the dose related neurotoxicity associated w/ Oxaliplatin, what are some other AE’s associated with this drug?

A
  • Nausea which is well controlled w/ 5HT3 receptor antagonists
  • May cause leukemia and pulmonary fibrosis months-years after administration
  • Allergic response: urticaria, hypotension, and bronchoconstriction
47
Q

What is the clinical use of Oxaliplatin?

A
  • Used tx colorectal and gastric cancer
  • Suppresses expression of thymidylate synthase (TS); allowing it to work synergistically in combo w/ 5-FU for tx of colorectal cancer

SBL (44 decks)

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