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Heme and Lymph Exam 1 > 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
What are 4 known MOA of the alkylating agent, Procarbazine?
- 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
Why does resistance to procarbazine develop rapidly when used as monotherapy?
Increased expression of **MGMT**
27
Which alkylating agent has the highest carcinogenic potential?
Procarbazine
28
What are 3 of the unique AE's associated with Procarbazine?
- ↑ risk **secondary cancer**: acute leukemia - **Augments** **sedative effects:** concomitant CNS suppressants should be avoided (i.e., alcohol) - **Disulfiram-like actions**: avoid alcohol
29
What is the MOA of Dacarbazine; how can resistance develop?
- **Prodrug**; functions as **methylating** **agent** after being convertedto metabolite **MTIC** - **Resistance** develops due to **removal** of **methyl groups** by **MGMT**
30
What is the most common AE of the alkylating agent, Dacarbazine?
**90%** of pt's experience **N/V** --\> 1-3 hours after tx, can last 12 hours
31
What is the MOA of the alkylating agent, Bendamustine?
- Forms **cross-links** w/ DNA = **single** and **double strand** breaks - **Inhibits** **mitotic checkpoints** and induces **mitotic catastrophe**
32
If there is resistance to alkylating agents, what is a non-classical alkylating agent which can be used?
**Bendamustine**; only **partial** cross-resistance w/ other alkylating agents
33
What are 3 AE's of Bendamustine and which are rapidly reversible?
- **Myelosuppression** and **Mucositis** (rapidly reversible) - **Mild N/V**
34
What are the known MOA for the alkylating agents that are platinum analogs; work during what stages of cell cycle?
- 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
The alkylating agents, which are platinum analogs have synergism with which 3 other classes?
Other **alkylating agents** + **fluoropyrimidine** + **taxanes**
36
Which precautions are taken with Cisplatin to prevent renal toxicity?
- 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
Which metal can inactivate Cisplatin and how does this affect the administration of the drug?
- **Aluminum** - Drug should **not** come in contact w/ **needles** or other **infusion** equipment containing **aluminum**
38
After administration which 4 areas contain high levels of Cisplatin?
**Kidney**, **liver**, **intestine**, and **testes**
39
What are 5 AE's of Cisplatin and how are they controlled?
- **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
What are some AE's associated with high doses/multiple cycles of Cisplatin?
- **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
How does the administration of Carboplatin differ from Cisplatin?
- Given via **IV** (like cisplatin) - **BUT** vigorous IV hydration is **NOT** required
42
What is a unique AE associated with the platinum analog, Carboplatin, and how does it compare to Cisplatin?
- **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
Carboplatin can be an effective alternative to Cisplatin in which patients?
Pt's w/ **impaired renal function** (adjust dose), **refractory nausea**, significant **hearing impairment**, and **neuropathy**
44
What is the dose-limited toxicity for Carboplatin vs. Oxaliplatin?
- **Carboplatin** = **myelosuppression** ---\> thrombocytopenia - **Oxalipatin** = **neurotoxicity** ---\> peripheral sensory neuropathy
45
What is the acute vs. cumulative dose form of the peripheral sensory neuropahty which may be seen with Oxaliplatin tx?
- **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
Other than the dose related neurotoxicity associated w/ Oxaliplatin, what are some other AE's associated with this drug?
- **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
What is the clinical use of Oxaliplatin?
- 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**

Heme and Lymph Exam 1 (14 decks)

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