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Pharm 2014 Unit 1 > cancer 2 > Flashcards

cancer 2 Flashcards

1
Q

combination chemotherapy is more

A

effective than single-drug treatment in most cancers

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2
Q

what are the 5 examples of combination regimens?

A
  1. ABVD
  2. CHOP
  3. MOPP
  4. CMF
  5. FEC
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3
Q

ABVD

A

doxyrubicin (adriamycin), bleomycin, vinblastine, decarbazine

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4
Q

CHOP

A

cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone

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5
Q

CMF

A

cyclophosphamide, methotrexate, 5-Fu

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6
Q

FEC

A

5-FU, epirubicin, cyclophosphamide

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7
Q

based on the mechanism of action, name the 7 classes of anticancer

A
  1. alkylating agents
  2. antimetabolites
  3. DNA intercalating agents
  4. microtubule inhibitors
  5. topoisomerase inhibitors
  6. hormones and their antagonist
  7. miscellaneous agents
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8
Q

What are alkylating agents?

A

a group of compounds that have the ability to transfer an alkyl group to DNA

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9
Q

alkylations promote

A

cross-linking of DNA strands resulting in DNA damage

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10
Q

sulfur mustards were used

A

as chemical warfare agents in WW1

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11
Q

what are some major classes of alkylating agents?

A
  1. cyclophosphamide
  2. ifosfamide
  3. carbustine
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12
Q

what is the mechanism of action of the alkylating agents?

A

produce strong electrophiles through the formation of carbonium or ethyleneimonium ion intermediates, which form covalent linkages by alkylation of nucleophilic moieties present in DNA

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13
Q

what is the major site of alkylation within DNA?

A

the N7 position of guanine

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14
Q

what are the toxicities of alkylating agents?

A
  1. bone marrow toxicity (neutropenia, thrombocytopenia, anemia)
  2. mucosal toxicity - oral mucosal ulceration
  3. nausea and vomiting
  4. toxic effects on reproductive systems (amenorrhea in women, male sterility)
  5. increased reisk of leukemia
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15
Q

what are the examples of resistance to alkylating agents?

A
  1. decreased permeability or uptake of the drugs
  2. increased rates of metabolism of the activated forms to inactive species
  3. enhanced activity of DNA repair pathways
  4. increased production of glutathione, which inactivates the alkylating agents throguh conjugation
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16
Q

what are the 4 types of alkylating agents?

A
  1. nitrogen mustards (mechlorethamine, cyclophosphamide, and ifosfamide)
  2. Nitrosoureas (carmustine and lomustine)
  3. Triazenes (dacarbazine and temozolomide)
  4. Platinum analogs (cisplatin, carboplatin, and oxaliplatin)
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17
Q

how do nitrogen mustards work?

A

they are bifunctional alkylating agents that undergo spontaneous conversion to active metabolites in body fluids or are enzymatic ally converted to active metabolites in the liver.

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18
Q

what are cyclophosphamide and Ifosfamide?

A
  1. prodrugs that must be converted to active alkylating metabolites by hepatic cytochrome P450 enzymes.
  2. the active alkylating metabolite is phosphramide mustard.
  3. these drugs can taken orally and have a relatively long plasma half-life compared to other alkylating agents
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19
Q

what are the therapeutic uses of cyclophosphamide?

A
  1. most widely used alkylating agent
  2. has a broad clinical spectrum
  3. used singly or as part of the combination regimen in the treatment of acute and chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, breast, lung and ovarian cancers
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20
Q

ifosfamide is used to treat

A

sarcoma and testicular cancer

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21
Q

toxicity of cyclophosphamide and ifosfamide?

A
  1. nausea, vomiting, myelosuppression

2. hemorrhagic cystitis

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22
Q

mechanism for hemorrhagic cystitis?

A

local irritation in the bladder due to toxic drug metabolite (acrolein) in the urine

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23
Q

what can be done to prevent hemorrhagic cystitis?

A

adequate hydration and administration of MENSA (sodium 2-mercaptoehtane sulfonate), which inactivates acrolein

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24
Q

what are the names of Nitrosoureas?

A

Carmustine, Lomustine

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25
Q

what are the therapeutic usage of the Carmustine and Lomustine?

A

they are highly lipohpilic and are able to cross the blood-brain barrier –> b/c of their excellent CNS penetration –> these drugs have been used to treat brain tumors

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26
Q

what are the toxicity of Carmustine and Lomustine?

A
  1. cause profound myelosuppression,
  2. severe nausea and vomiting,
  3. renal toxicity
  4. pulmonary fibrosis
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27
Q

what are types of Triazenes?

A

Dacarbazine and Temozolomide

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28
Q

Dacarbazine is a

A

prodrug that requires metabolic activation by cytochromes in the liver

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29
Q

Dacarbazine is part of the combination regimen

A

(ABVD) used for the treatment of Hodgkin’s disease, also used for malignant melanoma

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30
Q

Temozolmide has significant activity against malignant

A

gliomas, it is the standard agent in combination with radiation therapy

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31
Q

What are 3 Platinum analogs?

A

cisplatin, carboplatin, oxaliplatin

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32
Q

what are the mechanism of platinum analogs?

A
  1. these drugs are inorganic platinum derivatives
  2. although cisplatin and other platinum analogs do not form carbonium ion intermediates like other alkylaing agents (formally alkylate DNA), they covalently bind to nucleophilic sites on DNA
33
Q

loading dose creates the conc

A

for therapeutic

34
Q

loading dose =

A

Cp X Vd

35
Q

platinum analog are converted to active cytotoxic forms by reacting with water to form positively charged, hydrated intermediates that can react with

A

DNA guanine, forming intrastand and interstand corss-link

36
Q

Cisplatin has efficacy against a wide range of neoplasms and it is used for the treatment of

A
  1. testicular
  2. ovarian
  3. cervical
  4. bladder cancers
37
Q

what is specifically approved for ovarian cancer?

A

carboplatin

38
Q

what is specifically used for treating gastric and colorectal cancer?

A

oxaliplatin

39
Q

what are the two important side effects of cisplatin?

A
  1. renal toxicity

2. ototoxicity

40
Q

what is special about the renal toxicity of cisplatin?

A

it’s the renal tubular damage/necrosis and it’s the dose-limiting toxicity

41
Q

what is the toxicity of carboplatin?

A

myelosuppression (thrombocytopenia)

42
Q

what are two important toxicity of oxaliplatin?

A
  1. peripheral sensory neuropathy (cold-induced acute peripheral neuropathy)
  2. neutropenia
43
Q

what are antimetabolites?

A

they are structural analogs of folic acid or the purine/pyrimidine bases found in DNA

44
Q

b/c antimetabolites inhibit DNA synthesis (S-phase),

A

they are considered as cell-cycle specific drugs or DNA synthesis inhibitors

45
Q

what are the two antimetabolites that are folate analogs?

A
  1. methotrexate

2. pemetrexed

46
Q

methotrexate is the most widely used

A

antimetabolites in cancer therapy

47
Q

methotrexate is

A

a folic acid antagonist that inhibits dihydrofolate reductase

48
Q

what does dihydrofolate reductase do?

A

converts dietary folate to the tetrahydrofolate form required for thymidine and purine biosynthesis

49
Q

methotrexate is effective in treating childhood

A

acute lymphoblastic leukemia (ALL) and choriocarcinoma

50
Q

methotrexate is also a component of combination therapy regimens for

A
  1. Burkitt’s lymphoma

2. carcinomas of the breast, ovary, head and neck and bladder

51
Q

MTX can not penetrate the CNS,

A

it is administered intrathecally for treatment of meningeal leukemia and meningeal metastases of a wide range of tumors

52
Q

high dose MTX is used for

A

osteosarcoma

53
Q

what are the significant toxicity of MTX?

A
  1. bone marrow toxicity (myelosuppression, spontaneous hemorrhage)
  2. GI toxicity (oral ulceration, stomatitis)
  3. renal toxicity (high dose MTX can crystallize in the urine and cause renal damage
  4. hepatotoxicity
54
Q

what are the mechanism of resistance to MTX?

A
  1. reduced drug uptake by neoplastic cells
  2. increased production of DHFR (gene amplification)
  3. decreased affinity of DHFR for MTX
55
Q

Pemetrexed is a

A

multi-targeted folate analog

56
Q

what are the examples of pyrimidine analogs?

A
  1. 5-fluorouracil
  2. cytarabine
  3. gemcitabine
57
Q

5-FU is a

A

pro-drug requireing enzymatic conversion (ribosylation and phosphorylation) into active metabolites (5-FdUMP) to exert its cytotoxic activity.

58
Q

5-FdUMP inhitibs

A

thymidylate synthetase and prevents thymidine synthesis

59
Q

what are the therapeutic uses of 5-FU?

A

5-FU is given IV b/c of its severe toxicity to the GI tract and rapid metabolic degradation in the gut and liver

60
Q

5-FU is used as a component of combination therapy for treatment of

A

breast, colorectal, gastric, head and neck

61
Q

what is the topical application of 5-FU?

A

basal cell carcinoma

62
Q

what is a newer, orally effective form of 5-FU?

A

capectabine, a prodrug, which is converted to 5’-deoxy-5-fluorouridine

63
Q

what is the toxicity of 5-FU?

A
  1. anorexia and nausea
  2. mucosal ulcerations
  3. hand-foot syndrome erythema, sensitivity of the palms and soles can occur
64
Q

what is an analog of 2’-deoxycytidine?

A

Cytarabine

65
Q

what are the 2 significant toxicity of carmustine, lomustine (Nitrosoureas)?

A
  1. renal toxicity

2. pulmonary fibrosis

66
Q

what is 6-mercaptopurine?

A

purine analogs

67
Q

what is the primary therapeutic uses of 6-mercaptopurine?

A

primarily to maintain remission in pts with ALL

68
Q

what are the two mechanisms of resistance of 6-mercaptopurine?

A

decreased expression of HGPRT

69
Q

what is an important drug interaction of 6-MP

A

allopurinal, which is used to treat hyperuricemia –> allopurinol inhibits xanthine oxidase and thereby increases plasma MP levels

70
Q

what should be done to pts receiving allpurinol?

A

decrease the dose of 6-MP

71
Q

what is 6-MP?

A

purine analog (pro-drug)

72
Q

6-MP requires

A

enzymatic conversion to ribonucelotide by HGPRT

73
Q

what is one of the pyrimidine analogs which is converted to Ara-CMP by deoxycytidine kinase?

A

Cytarabine (Ara-C)

74
Q

what is the most important therapeutic usage of cytarabine (Ara-C)?

A

AML

75
Q

what is 5-FU?

A

pyrimidine analog, a pro-drug which is enzymatically converted into active metabolite 5-FdUMP

76
Q

5-FU must be given

A

IV due to rapid metabolic degradation in the gut and liver

77
Q

toxicity of 5-FU?

A

hand foot syndrome - erythema, sensitivity to the palms and soles

78
Q

how can the toxic effect of MTX be prevented?

A

by leucovorin

79
Q

what are the two important toxicity of nitrosoureas (carmustine, lomustine)?

A

renal toxicity, pulmonary fibrosis

Pharm 2014 Unit 1 (13 decks)

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