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Block 7 Week 1 > Duan: Cancer Chemotherapy > Flashcards

Duan: Cancer Chemotherapy Flashcards

1
Q

What is the mechanism of action of the alkylating agents?

A

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

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2
Q

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

A

electron-rich nitrogen at the N7 position

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3
Q

List two major groups of alkylating agents

A

Nitrogen mustards

Nitrosoureas

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4
Q

Are alkylating agents cell cycle/phase specific?

A

no; active even for the resting cells in G0

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5
Q

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

A

Nitrogen mustards

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6
Q

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.

A

cross-linking

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7
Q

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

A

cytotoxicity

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8
Q

What are nitrogen mustards used for?

A

lymphomas

leukemias

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9
Q

What are the adverse reactions of nitrogen mustards?

A

teratogens
immunosuppressive
carcinogenic

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10
Q

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

A

Mechlorethamine

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11
Q

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

A 
MOPP
Mechlorethamine
Oncovin
Procarbazine
Prednisone
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12
Q

Side effects of mechlorethamine?

A

bone marrow depression
infertility
GI toxicity

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13
Q

Broad spectrum nitrogen mustard; given orally or IV

A

cyclophosphamide

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14
Q

What is the method of action of cyclophosphamide?

A

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

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15
Q

What is cyclophosphamide used for clinically?

A 
non-neoplastic diseases (nephrotic syndrome)
Non-Hodgkin's lymphomas
Acute lymphoid leukemia
Breast cancer
Carcinoid
Neuroblastoma
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16
Q

Adverse effects of cyclophosphamide?

A

bone marrow depression
alopecia
disturbed GI

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17
Q

An analog of cyclophosphamide; activated in liver by ring hydroxylation

A

ifosfamide (ifex)

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18
Q

What is Ifosfamide used to treat?

A

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

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19
Q

Adverse effects of Ifosfamide?

A

similar to cyclophosphamide

+ platelet suppression, severe urothelial damage and internal bleeding

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20
Q

What is the mechanism of action of the nitrosoureas?

A

spontaneous degradation forms 2-chloroethyl carbonium ion

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

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21
Q

Adverse reactions to nitrosoureas?

A

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

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22
Q

This nitrosourea has high lipophilicity

A

Carmustine

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23
Q

This nitrosourea is given orally

A

Lomustine

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24
Q

What are the nitroureas Carmustine and Lomustine used for clinically?

A

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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25
Q

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

A

Streptozotocin

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26
Q

What is the clinical use for the nitrosourea Streptozotocin?

A

insulinomas (islet cell carcinoma)

metastatic cancer of pancreatic islet cells

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27
Q

What is the alkyl sulfonate Busulfan used for clinically?

A

chronic myelogenous leukemia
other myeloproliferative disorders

**it is selectively myelosupressive and inhibits granulocytopoiesis

28
Q

What can alkyl sulfonates like Busulfan cause?

A

myelosuppression

busulfan lung: rare, fatal pulmonary fibrosis

29
Q

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

A

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

30
Q

Which phase in the cell cycle do antimetabolites block?

A

S-phase

31
Q

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

A

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

32
Q

Clinical use of purine antagonist 6-MP?

A

acute lymphoid leukemia in children

33
Q

Adverse effects of purine antagonists?

A

bone marrow suppression
immunosuppression
GI disturbance
liver toxicity

34
Q

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

A

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

35
Q

What is 6-thioguanine used for clinically?

A

leukemia

36
Q

Adverse effects of 6-thioguanine?

A

bone marrow suppression

mild nausea

37
Q

What is the mechanism of action of 5-Fluorouracil?

A

pyrimidine analog; inhibits thymidylate synthesis, causing decreased dTMP and termination of DNA synthesis

**S-phase specific

38
Q

What does 5-fluorouracil require to become active?

A

enzymatic conversion to a nucleotide

39
Q

Clinical use for 5-fluorouracil?

A 
basal cell carcinoma
solid tumors of many organs
lymphomas
leukemias
keratoses of the skin
40
Q

Adverse reactions of 5-fluorouracil?

A

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

41
Q

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

A

nucleotide formed in the target cell terminates DNA chain elongation; continuous IV

**S phase specific

42
Q

WHat is cytarabine used for clinically?

A

first-line drug for acute myelogenous leukemia and lymphomas

43
Q

Adverse effects of pyrimidine antagonist cytarabine?

A

bone marrow depression

severe bone marrow hypolasia

44
Q

Methotrexate is a folate antagonist. How does it work?

A

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

45
Q

What is methotrexate used for clinically?

A 
choriocarcinoma (solid tumor)
acute lymphoblastic leukemia
choriocarcinoma
osteocarcinoma
RA
psoriasis
46
Q

What is the method of resistance to methotrexate?

A

decreased uptake

47
Q

Adverse reactions to methotrexate?

A

neurotoxicity
nephrotoxicity
interstitial pneumonitis
hepatotoxicity

48
Q

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

A

Leucovorin

49
Q

What is used together to “rescue normal cells?”

A

MTX + leucovorin

50
Q

Inhibit dehydrofolate reduction and blocks purine & TMP synthesis

A

folate antagonists (MTX)

51
Q

Inhibits dTMP synthesis

A

5-fluorouracil

52
Q

Inhibits DNA synthesis

A

cytarabine

53
Q

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

A

inhibit topoisomerase II, which unwinds DNA for transcription

**stops replication of DNA

54
Q

What is the antibiotic daunorubicin used to treat most commonly?

A

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
55
Q

Two antibiotics used for acute myeloid leukemia

A

daunorubicin

idarubicin

56
Q

Antibiotic used for breast cancer

A

epirubicin

57
Q

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

A

cardiomyopathy

58
Q

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

A

Bleomycins

59
Q

What is the mechanism of action of bleomycins?

A

free radical induced DNA strand breaks

inhibits incorporation of thymidine into DNA strands

60
Q

What is bleomycin used for clinically?

A

combined w vinblastine and cisplatin to treat testicular cancer
lymphomas
squamous carcinomas of cervix, head and neck, and lungs

**important in multidrug regimens (ABVD)

61
Q

Main adverse effect of bleomycin?

A

fatal lung toxicity

62
Q

What is the mechanism of action of mitomycin C?

A

cross-links DNA

may also produce oxygen free radicals which cleave DNA

63
Q

What phase of the cell cycle does mitomycin affect?

A

G1

64
Q

What is mitomycin used for clinically?

A

adenocarcinomas of the breast, colon, stomach, lung

65
Q

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

A

daunorubicin

66
Q

What is the method of action of etoposide?

A

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

67
Q

What is etoposide used for clinically?

A 
testicular cancer
lung cancer
lymphomas
acute nonlymphocytic leukemia 
breast cancer

Block 7 Week 1 (9 decks)

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