Duan: Cancer Chemotherapy Flashcards by Megan Foggia

What is the mechanism of action of the alkylating agents?

impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules

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What position on the guanine molecule is particularly susceptible to alkylation?

electron-rich nitrogen at the N7 position

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List two major groups of alkylating agents

Nitrogen mustards

Nitrosoureas

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Are alkylating agents cell cycle/phase specific?

no; active even for the resting cells in G0

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The first chemotherapy agent used in humans; prototype alkylating agent; main toxicity comes from DNA cross linkage

Nitrogen mustards

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With bifunctional alkylating agents, the second 2-chloroethyl side chain can undergo a similar intramolecular cyclization and alkylate a second guanine residue and result in a (blank) of two nucleic acid chains, or the link of a nucleic acid to a protein.

cross-linking

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(blank) of bifunctional alkylating agents correlates very closely with inter-strand cross linkage of DNA.

cytotoxicity

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What are nitrogen mustards used for?

lymphomas

leukemias

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What are the adverse reactions of nitrogen mustards?

teratogens
immunosuppressive
carcinogenic

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This is a nitrogen-based analogue of mustard gas; it is the most reactive

Mechlorethamine

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What are the 4 drugs used to treat Hodgkin’s disease?

MOPP
Mechlorethamine
Oncovin
Procarbazine
Prednisone

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Side effects of mechlorethamine?

bone marrow depression
infertility
GI toxicity

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Broad spectrum nitrogen mustard; given orally or IV

cyclophosphamide

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What is the method of action of cyclophosphamide?

prodrug, which is converted to phosphoramide mustard and acrolein by P450; DNA cross-linking (N7 of guanine)

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What is cyclophosphamide used for clinically?

non-neoplastic diseases (nephrotic syndrome)
Non-Hodgkin's lymphomas
Acute lymphoid leukemia
Breast cancer
Carcinoid
Neuroblastoma

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Adverse effects of cyclophosphamide?

bone marrow depression
alopecia
disturbed GI

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An analog of cyclophosphamide; activated in liver by ring hydroxylation

ifosfamide (ifex)

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What is Ifosfamide used to treat?

testicular, cervical, ovarian, breast, bone cancers, pediatric and adult sarcomas; also used in combo with mesna to reduce urinary toxicity

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Adverse effects of Ifosfamide?

similar to cyclophosphamide

+ platelet suppression, severe urothelial damage and internal bleeding

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What is the mechanism of action of the nitrosoureas?

spontaneous degradation forms 2-chloroethyl carbonium ion

**cross-link DNA strands, break DNA strands, carbamoylate protein

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Adverse reactions to nitrosoureas?

highly carcinogenic and mutagenic; PROFOUND myelosuppresion, renal failure, alopecia, hepatotoxicity, pulmonary toxicity

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This nitrosourea has high lipophilicity

Carmustine

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This nitrosourea is given orally

Lomustine

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What are the nitroureas Carmustine and Lomustine used for clinically?

important in the treatment of brain tumor (highly lipophilic –> can cross the BBB), GI neoplasm, alternative drug in treating Hodgkin’s disease

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This nitrosourea is not orally effective; it methylates DNA and RNA and is particularly toxic to pancreatic islet cells

Streptozotocin

What is the clinical use for the nitrosourea Streptozotocin?

insulinomas (islet cell carcinoma) | metastatic cancer of pancreatic islet cells

What is the alkyl sulfonate Busulfan used for clinically?

chronic myelogenous leukemia other myeloproliferative disorders **it is selectively myelosupressive and inhibits granulocytopoiesis

What can alkyl sulfonates like Busulfan cause?

myelosuppression | busulfan lung: rare, fatal pulmonary fibrosis

What are the three groups of antimetabolites? How to antimetabolites work?

purine analogs, pyrimidine analogs, folate antagonists; they act as enzyme inhibitors and slow down the synthesis of nucleic acids

Which phase in the cell cycle do antimetabolites block?

S-phase

What is the mechanism of action of 6-Mercaptopurine (6-MP), a purine antagonist?

structural analog of adenine; blocks the first step in de novo synthesis of purines by impeding DNA replication and RNA transcription

Clinical use of purine antagonist 6-MP?

acute lymphoid leukemia in children

Adverse effects of purine antagonists?

bone marrow suppression immunosuppression GI disturbance liver toxicity

What is the mechanism of action of the purine antagonist, 6-thioguanine?

enzymatic (HGPRT) conversion to a nucleotide (6-TGMP) which in turn becomes incorporated into DNA as dTGTP. It is also an enzyme inhibitor.

What is 6-thioguanine used for clinically?

leukemia

Adverse effects of 6-thioguanine?

bone marrow suppression | mild nausea

What is the mechanism of action of 5-Fluorouracil?

pyrimidine analog; inhibits thymidylate synthesis, causing decreased dTMP and termination of DNA synthesis **S-phase specific

What does 5-fluorouracil require to become active?

enzymatic conversion to a nucleotide

Clinical use for 5-fluorouracil?

``` basal cell carcinoma solid tumors of many organs lymphomas leukemias keratoses of the skin ```

Adverse reactions of 5-fluorouracil?

bone marrow depression alopecia disturbance of GI system hand and foot syndrome

Cytarabine is a pyrimidine antagonist (cytidine analog). What is its mechanism of action? How is it administered?

nucleotide formed in the target cell terminates DNA chain elongation; continuous IV **S phase specific

WHat is cytarabine used for clinically?

first-line drug for acute myelogenous leukemia and lymphomas

Adverse effects of pyrimidine antagonist cytarabine?

bone marrow depression | severe bone marrow hypolasia

Methotrexate is a folate antagonist. How does it work?

structural analog of folic acid; reversibly inhibits DHF reductase resulting in decreased dTMP; inhibits purine and thymidylate synthesis

What is methotrexate used for clinically?

``` choriocarcinoma (solid tumor) acute lymphoblastic leukemia choriocarcinoma osteocarcinoma RA psoriasis ```

What is the method of resistance to methotrexate?

decreased uptake

Adverse reactions to methotrexate?

neurotoxicity nephrotoxicity interstitial pneumonitis hepatotoxicity

a reduced (active) analog of folic acid. It allows nucleic acid synthesis to proceed even in the presence of methotrexate

Leucovorin

What is used together to "rescue normal cells?"

MTX + leucovorin

Inhibit dehydrofolate reduction and blocks purine & TMP synthesis

folate antagonists (MTX)

Inhibits dTMP synthesis

5-fluorouracil

Inhibits DNA synthesis

cytarabine

What is the mechanism of action of the antibiotics doxorubicin and etoposide

inhibit topoisomerase II, which unwinds DNA for transcription **stops replication of DNA

What is the antibiotic daunorubicin used to treat most commonly?

specific types of leukemia (acute myeloid and acute lymphocytic leukemia) ``` **can also treat Hodgkin's disease soft tissue carcinoma breast cancer lung cancer ovarian, bladder, thyroid cancers ```

Two antibiotics used for acute myeloid leukemia

daunorubicin | idarubicin

Antibiotic used for breast cancer

epirubicin

What is the main adverse effect when you give a cumulative dose of 450mg/m2 of Doxorubicin?

cardiomyopathy

A glycosylated linear nonribosomal peptide antibiotic produced by the bacterium Streptomyces verticillus

Bleomycins

What is the mechanism of action of bleomycins?

free radical induced DNA strand breaks | inhibits incorporation of thymidine into DNA strands

What is bleomycin used for clinically?

combined w vinblastine and cisplatin to treat testicular cancer lymphomas squamous carcinomas of cervix, head and neck, and lungs **important in multidrug regimens (ABVD)

Main adverse effect of bleomycin?

fatal lung toxicity

What is the mechanism of action of mitomycin C?

cross-links DNA | may also produce oxygen free radicals which cleave DNA

What phase of the cell cycle does mitomycin affect?

What is mitomycin used for clinically?

adenocarcinomas of the breast, colon, stomach, lung

used as the starting material for semi-synthetic manufacturing of doxorubicin, epirubicin and idarubicin.

daunorubicin

What is the method of action of etoposide?

inhibits topoisomerase II, arresting the cell cycle at S/G2 **it binds to topoisomerase II and prevents the enzyme from resealing the double-stranded DNA breaks

What is etoposide used for clinically?

``` testicular cancer lung cancer lymphomas acute nonlymphocytic leukemia breast cancer ```