Alkylating Agents and Cisplatin Flashcards

1
Q

Alkylating drugs: Nitrogen Mustards

A

Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine

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2
Q

Alkylating drugs: Ethyleneiminies and Methylmelamines

A

Altretamine, Thiotepa

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3
Q

Alkylating drugs: Alkyl Sulfonates

A

Busulfan

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4
Q

Alkylating drugs: Nitrosoureas

A

Carmustine (BCNU), streptozocin

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5
Q

Alkylating drugs: Triazenes

A

Dacarbazine (DTIC), Temozolomide

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6
Q

Alkylating drugs: Methylhydrazines

A

Procarbazine

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7
Q

Cytotoxic drugs

A

kills cells that are growing rapidly. stops cancer from dividing and growing and may cause tumors to shrink in size.

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8
Q

Cytotoxic drugs primary curative for which diseases?

A

Leukemias, lymphomas, choriocarcinomas, testicular cancer

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9
Q

cytotoxic drug usage?

A

for palliative purposes-to reduce tumor size/growth and untoward symptoms

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10
Q

What are categories of cytotoxic drugs?

A

Alkylating agents, platinum coordination complexes, antimetabolites, natural products

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11
Q

Alkylating agents MOA:

A

alkylates DNA, RNA, and proteins

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12
Q

Platinum Coordination Complexes

A

Do not alkylate DNA but forms covalent metal adducts with DNA

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13
Q

Antimetabolties MOA

A

Affects DNA or RNA synthesis

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14
Q

Natural Products MOA:

A

Affects DNA, RNA, and protein involving cell growth and division

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15
Q

Alkylating drugs AE?

A

Marrow, mucosa, hair follicles, nervous system, leukemogenesis

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15
Q

Alkylating drugs AE?

A

Marrow, mucosa, hair follicles, nervous system, leukemogenesis

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16
Q

Mono-functional alkylating agents?

A

react with only one strand of DNA (simple methylation)
greater capacity for mutagenesis and carcinogenesis

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17
Q

Bi-functional alkylating agent?

A

react with an atom on both strands of DNA-produces cross-link that covalently links two strands of DNA double helix
Cytotoxic effects predominate

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18
Q

Mono-functional methylating agents:

A

procarbazine, dacarbazine, temozolomide

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19
Q

which mono-functional methylating agent is highly carcinogenic?

A

Procarbazine

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20
Q

alkylating agents form?

A

highly reactive carbonium ion intermediates

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21
Q

alkylating drugs link ?

A

covalently to sites of high electron density-phosphates, amines, sulfhydryl, hydroxyl groups

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22
Q

alkylating cytotoxic effects related to alkylation of?

A

reactive amines, oxygens, or phosphates

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23
Q

N7 atom of guanine susceptible to

A

formation of covalent bond with bifunctional alkylating agents

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24
which alkylating agents are prodrugs?
Cyclophosphamide and ifosfamide
25
cyclophosphamide and ifosfamide undergo what metabolism?
hepatic
26
what factors affect alkylating agents activities in vivo?
lipophilicity, sites of macomolecular attack, mechanism of DNA repair, active transport
27
Nitrogen mustards are what type of alkylating agents?
bi-functional
28
what is the treatment regimen for hodgkin lymphoma?
MOPP Mustargen (Mechlorethamine) Oncovin (Vincristine) Procarbazine (Matulane) Prednisone (Deltasone)
29
Cyclophosphamide showed complete remissions and cures in which cancer?
Burkitt Lymphoma
30
which alkylating agent is good in pediatrics?
Chlorambucil (really no toxicity)
31
Nitrogen Mustard: Cyclophsophamide generates?
Phosphoramide mustard and Acrolein
32
What is phosphoramide mustard responsible for?
antitumor effects
33
What does acrolein cause?
hemorrhagic cystitis
34
what is the intermediate of cyclophosphamide?
4-hydroxy intermediate
35
Altretamine can be palliative treatment in persistent or recurrent ____?
ovarian cancer following cisplatin based combo therapy
36
Busulfan is a ?
alkyl sulfonate
37
Busulfan may induce?
cross-linkage of DNA to nuclear proteins
38
Busulfan metabolized by?
Glutathione (GSH) conjugation by GSTA1A in the liver and further by CYP dependent pathways to inactivate metabolites
39
What is the major action of Carmustine (BCNU)?
bi-functional alkylation-of DNA at the O6-guanine position----repair by MGMT
40
Carmustine and lomustine are highly?
Lipophillic (crosses BBB)
41
Carmustine (BCNU) is used in treatment of?
Malignant gliomas (brain tumors) -enters CSF -Use IV
42
What is the major action of streptozocin?
methylnitrosourea moitey to the 2-carbon of glucose of DNA
43
Triazenes are prodrugs:
Dacarbazine and Temozolomide
44
Triazenes function?
kill cells in all phases of the cell cycle
45
Triazenes especially Dacarbazine causes?
removal of methyl group from O6 guanine bases in DNA by MGMT----causing drug resistance
46
Dacarbazine administration? and excretion?
IV 50% excreted intact in urine by tubular secretion
47
Alkylating agents used as a single agent has _____ resistance? Due to?
High Decreased permeation of actively transported drugs Increased intracellular concentrations of nucleophilic substances such as elevated glutathione levels and increased activity of glutathione transferases (detoxification)
48
resistance is also due to?
increased activity of DNA repair pathways (MGMT, mutations of p53) increased rates of metabolic degradation of the activated forms of cyclophosphamide and ifosfamide to their inactive keto and carboxy metabolites by aldehyde dehydrogenase loss of ability to recognize adducts formed by nitrosoureas and methylating agents (defective mismatch repair and checkpoint function) impaired apoptotic pathways (overexpression of Bcl-2: apoptosis inhibitor)
49
which drugs have high expression of MGMT?
BCNU, Dacrabazine, temozolomide, and procarbazine
50
Alkylating agents at high doses ________ ________
kills more slow proliferating cells
51
alkylating agents suppress?
cellular and humoral immunity-chance for opportunisitc infections
52
alkylating agents may cause:
Myelosuppression (bone marrow activity decreased) loss of hair follicles, mucosal damage nausea and vomitting can induce leukemia (melphalan and procarbazine)
53
Which alkylating agent is the most neurotoxic?
Ifosfamide-alters mental status and coma, seizures
54
Busulfan or BCNU high doses can cause vascular endothelial damage which can be reversed by?
Defibrotide
55
Acrolein metabolite may cause hemorrhagic cystitis what should you coadminister with Cyclophosphamide and ifosfamide to prevent?
Mesna
56
What is the major organ toxicity of alkylating agents?
Hepatic VOD (vein occlusive disease)
57
What drugs are platinum complexes?
cisplatin, carboplatin, oxaliplatin
58
Platinum complexes DO NOT?
form carbonium ion intermediates or alkylate DNA (no alkyl group)
59
Platinum coordination complexes have a broad antineoplastic activity.
True
60
DNA Platinum adducts inhibit?
replication and transcription-leading to breaks and miscoding
61
Overexpression of nucleotide excision repair (NER) causes
poor response to cisplatin/oxaliplatin therapies
62
What do you give prior to treatment of Cisplatin?
Normal saline to establish chloride diuresis (prevention of renal toxicitiy)
63
Carboplatin is eliminated by?
renal excretion
64
Carboplatin is ____ _____ reactive than cisplatin
much less (drug in plasma remains in parent form and unbound to proteins) less side effects too
65
Cisplatin can cure when used in combo with alkylating agents ?
testicular cancer
66
to prevent renal toxicity with use of Cisplatin give?
Amifostine
67
Cisplatin adverse effect?
development of AML (4 years of treatment)
68
Oxaliplatin can cause what after months to years of treatment?
leukemia
69
Oxiplatin is used in which cancers?
colorectal and gastric