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Chemotherapy Viruses > Chemotherapy II > Flashcards

Chemotherapy II Flashcards

1
Q

General MOA of alkylating agents

A

-Bind covalently to the DNA to produce DNA-drug interstrand and DNA intrastrand crosslinks
Cell cycle non-specific
Cytotoxic

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2
Q

List the bis(chloroethyl)amine drugs

A

List the bis(chloroethyl)amine drugs Cyclophosphamide
Mechlorethamine (nitrogen mustard)
Chlorambucil
Melphalan

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3
Q

MOA of bis(chloroethyl)amines

A

MOA of bis(chloroethyl)amines Bifunctional alkylating agents
Preferentially alkylate the N-7 position of guanine

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4
Q

List the nitrosourea drugs

A

BCNU

CCNU

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5
Q

MOA of nitrosourea drugs

A

Bifunctional alkylating agents

Alkylate N-7 position of guanine

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6
Q

Critical alkylation site of guanine

A

O-6 position

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7
Q

Describe the cross resistance of nitrosourea

A

BCNU and CCNU will be cross-resistant but the nitrosureas are generally only partially cross-resistant with the bis(chloroethyl)amines

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8
Q

What is resistance to nitrosureas due to

A

Constitutively high levels of a repair suicide enzyme termed an alkyltransferase

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9
Q

Why were nitrosureas of particular interest?

A

Highly lipophilic and cross the BBB

-Treat glioblastoma and other brain tumors

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10
Q

MOA of platinum coordination compounds

A

Bifunctional alkylating agents

Alkylation occurs primarily at the N-7 position of guanine

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11
Q

General mechanisms of resistance to alkylating agents

A
  • Nucleotide excision repair enzymes

- Binding of the alkylating agent to sulfur containing compounds

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12
Q

Class of Cyclophosphamide

A

Bifunctional alkylating agent (oxazaphosphorine)

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13
Q

Cycle specificity of Cyclophosphamide

A

CCNS

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14
Q

Macromolecular target of Cyclophosphamide

A

DNA

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15
Q

Bioactivation of Cyclophosphamide

A
  • Activated by microsomal enzymes (P450 oxidase) to 4- hydroxycyclophosphamide which is in equilibrium with aldophosphamide
  • Aldophosphamide is cleaved to acrolein and phosphoramide mustard
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16
Q

MOA of Cyclophosphamide

A

Phosphoramide mustard bifunctionally alkylates the N7 position of guanine and can form interstrand and intrastrand crosslinks

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17
Q

Excretion of Cyclophosphamide

A

Metabolites are excreted in the urine

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18
Q

SEs of Cyclophosphamide

A 
Nausea, vomiting, hair loss, myelosuppression, hematuria
Acute leukemia (mutagenic effects)
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19
Q

MOA of Cyclophosphamide induced hematuria

A

Acrolein -> hematuria

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20
Q

Prevention of Cyclophosphamide induced hematuria

A
  1. Administering the drug in the morning
  2. Drinking 6-8 glasses of water a day and urinating frequently
  3. Continuous bladder irrigation (when used in high dose)
  4. The use of mesna (uroprotective agent)
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21
Q

Uses of Cyclophosphamide

A

Breast cancer

Non-Hodgkin’s lymphoma

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22
Q

Route of administration of Cyclophosphamide

A

Oral

IV

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23
Q

Compounds in the same class as Cyclophosphamide

A

Nitrogen mustard
Chlorambucil
Melphalan

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24
Q

SEs of all drugs in the same class as Cyclophosphamide

A

Myelosuppression as dose limiting toxicity

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25
Q

Use of Chlorambucil and Melphalan

A

Orally

Chronic treatment of chronic lymphocytic leukemia, multiple myeloma

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26
Q

Class of Ifosfamide

A

Alkylating agent

Isomer of Cyclophosphamide

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27
Q

Cycle specificity of Ifosfamide

A

CCNS

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28
Q

Macromolecular target of Ifosfamide

A

DNA

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29
Q

Bioactivation of Ifosfamide

A
  • Activated by microsomal enzymes (P450 oxidase) to 4- hydroxycyclophosphamide which is in equilibrium with aldophosphamide
  • Aldophosphamide is cleaved to acrolein and phosphoramide mustard
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30
Q

MOA of Ifosfamide

A

DNA crosslinking

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31
Q

Excretion of Ifosfamide

A

Excreted via the urine

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32
Q

SEs of Ifosfamide

A

Myelosuppression is dose limiting
Lethargy and confusion (at high doses)
Nausea, vomiting, hair loss
High occurence of hemorrhagic cystitis

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33
Q

Dose limiting SE of Ifosfamide

A

Myelosuppression

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34
Q

Dosing of Ifosfamide vs. Cyclophosphamide

A

Ifosfamide requires much higher doses

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35
Q

Coadministered drug with Ifosfamide

A

MESNA (uroprotective agent)

To prevent hemorrhagic cystitis

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36
Q

MOA of MESNA

A

Dimerizes and is inactive in the blood
Dimerizes and is hydrolyzed in the urine to bind to acrolein and other alkylating agent metabolites to protect urothelium

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37
Q

Uses of Ifosfamide

A

Sarcomas

Relapsed testicular cancer

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38
Q

Class of Temozolomide

A

Alkylating agent (monofunctional)

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39
Q

Cycle specificity of Temozolomide

A

CCNS

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40
Q

Macromolecular target of Temozolomide

A

DNA

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41
Q

Bioactivation of Temozolomide

A

Spontaneous hydrolysis to DNA reactive species

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42
Q

MOA of Temozolomide

A

The DNA reactive species methylates the DNA and inhibits DNA function and DNA synthesis

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43
Q

Excretion of Temozolomide

A

1/3 of administered dose is recovered from the urine

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44
Q

SEs of Temozolomide

A

Myelosuppresion (dose limiting)

Nausea, vomiting, hair loss

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45
Q

Routes of administration of Temozolomide

A

Oral or IV

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46
Q

In treatment with Temozolomide what may be needed prophyactically (esp. if given for a long period of time)

A

Prophylaxis for pneumocystis carinii pneumonia

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47
Q

Coadministration of what is possible in treatment with Temozolomide

A

Radiation

48
Q

Use of Temozolomide

A

Malignant brain tumors- glioblastoma

49
Q

Class of Cisplatin

A

Platinum coordination compounds

Bifunctional alkylating agent

50
Q

Cycle specificity of Cisplatin

A

CCNS

51
Q

Macromolecular target of Cisplatin

A

DNA

52
Q

Bioactivation of Cisplatin

A

Parent compound is not active

Solution in the presence of low chloride ion concentration, the molecule undergoes sequential aquation

53
Q

MOA of Cisplatin

A

Binds covalently to DNA to produce cytotoxic interstrand and intrastrand crosslinks
Preferential binding to N7 position of adenine and guanine
Leaving groups are cis
Platinum in the +2 oxidation state

54
Q

Protein binding of Platinum coordination compounds

A

Tightly bound to proteins in the plasma

55
Q

Excretion of Cisplatin

A

Kidneys

56
Q

SEs of Cisplatin (heavy metal effects)

A
  • Intense nausea and vomiting
  • *Renal toxicity is dose limiting
  • Myelosuppression in
57
Q

Dose limiting Cisplatin SE

A

Renal Toxicity

58
Q

How is renal toxicity avoided in use of

Cisplatin

A
  • Drug is given with saline/mannitol diuresis
  • Chloruresis protects the kidneys
  • Hydration
59
Q

Contraindications of

Cisplatin

A
  • Pre-existing cardiac/pulmonary problems (lack of hydration and risk of kidney toxicity)
  • Dose reductions of the drug are necessary for patients with renal insufficiency
60
Q

Uses of Cisplatin

A 
Testicular cancer (curative) 
Bladder cancer
Head and neck cancer
Ovarian cancer
Small cell and non-small cell lung cancer
61
Q

Platinum coordintion compounds

A

Cisplatin
Carboplatin (cis-diammine-1,1-cyclobutane-dicarboxylato-platinum (II))
Oxaliplatin

62
Q

Differences between Carboplatin and Cisplatin

A
  • Kinetics of crosslinking (takes longer)

- Does not have to be given with saline hydration- no renal toxicity

63
Q

Cross resistance of Carboplatin and Cisplatin

A

Produces the same DNA lesions so cross-resistant

64
Q

SEs of Carboplatin

A

Not renal toxic

Myelosuppression is dose limiting

65
Q

Excretion of Carboplatin

A

Excreted via the kidney

Linear relationship between carboplatin plasma clearance and glomerular filtration rate

66
Q

Unique feature of Carboplatin dosage

A

Calculated using a targeted AUC
(area under the curve, free carboplatin plasma concentration X time; mg/ml/min)
Relationship between AUC and toxicity (thrombocytopenia)
Aim for AUC values from 5-7 mg/ml/min

67
Q

Calculation of Carboplatin dose

A

Dose (mg) = AUC X (GFR + 25)

68
Q

Uses of Carboplatin

A 
Testicular cancer
Bladder cancer
Head and neck cancer
Ovarian cancer
Small cell and non-small cell lung cancer
69
Q

Class of Oxaliplatin

A

Third generation platinum coordination compound

70
Q

Excretion of Oxaliplatin

A

Kidneys (not nephrotoxic)

71
Q

SEs of Oxaliplatin

A

Myelosuppression is common but not severe

Neurotoxicity - acute and chronic sensory

72
Q

Dose limiting SE of Oxaliplain

A

Myelosuppression

73
Q

Describe Oxaliplatin induced acute neurotoxicity

A

Begins during the drug administration
Cold induced: paresthesias, electric shock like sensations in the extremities when cold, laryngeal dysesthesia when drinking cold liquids
First chew phenomenon
Last ~1 week after administration

74
Q

Clinical indication of Oxaliplatin

A

Significant antineoplastic activity against colorectal cancer (doubling survival in patients with metastatic colorectal cancer)

75
Q

Describe Oxaliplatin induced chronic neurotoxicity

A

Describe Oxaliplatin induced chronic neurotoxicity Cumulative toxicity and occurs after repeated administrations of drug and consists of stocking and glove paresthesias
Gets better with time but slowly and does not completely resolve

76
Q

List the plant alkaloids

A

Vincristine
Vinblastine (periwinkle plant)
Taxol (yew tree)
Etoposide is semisynthetic

77
Q

Cell specificity of Vincristine

A

CCS (M-phase)

78
Q

Cell specificity of Vinblastine

A

CCS (M-phase)

79
Q

Cell specificity of Taxol

A

CCS (M-phase)

80
Q

Class of Vincristine

A

Plant Alkaloid, Spindle poison

81
Q

Macromolecular target of Vincristine

A

Tubulin

82
Q

MOA of Vincristine

A

Binds to dimeric form of tubulin and prevents polymerization of tubulin/ microtubular assembly
Causes the dissolution of mitotic spindle

83
Q

Excretion of Vincristine

A

Bile

84
Q

Dose reduction of Vincristine needed in

A

Patients with elevated Bilirubin

85
Q

SEs of Vincristine

A

Neuropathy is dose limiting (worry about severe - i.e. foot drop but not tingling)
Sensory and autonomic neuropathies (motor are not common)
Stimulation of antidiuretic hormone release -> hyponatremia
NO myelosuppression
Hair loss, nausea and vomiting NOT a problem

86
Q

What SE of Vincristine is dose limiting

A

Neuropathy

87
Q

Uses of Vincristine

A

Lymphoma
Hodgkin’s disease
lymphoblastic leukemia

88
Q

SEs of Vinblastine

A

Much less neurotoxic than vincristine

Dose limiting myelosuppression

89
Q

Use of Vinorelbine

A

Lung cancer and breast cancer

90
Q

MOA of vinblastine

A

nhibit mitotic spindle formation (spindle poison)

91
Q

MOA of taxol

A

Prevent breakdown of mitotic spindle (spindle poison)

92
Q

Schedule of taxol and vincristine administration

A

Drugs act on a relatively brief phase of the cell cycle and are specific - give as continuous infusion

93
Q

MOA of etoposide (VP-16)

A

Inhibits topoisomerase II and DNA strand breakage occurs

not a spindle poison

94
Q

Class of Paclitaxel

A

Plant alkaloid

95
Q

Macromolecular target of Paclitaxel

A

Tubulin

96
Q

MOA of Paclitaxel

A

Prevents tubulin disassembly

97
Q

Protein binding of Paclitaxel

A

Tightly bound to plasma proteins

98
Q

Excretion of Paclitaxel

A

Biliary system

99
Q

Metabolism of Paclitaxel

A

Hepatic

100
Q

SEs of Paclitaxel

A

Myelosuppression (dose limiting)
Nausea and vomiting, stomatitis, peripheral sensory neuropathy, myalgias, and arthralgias
Hair loss
Allergic reactions: due to polyoxyethylated castor oil vehice needed to make paclitaxel soluble

101
Q

Dose limiting SE of Paclitaxel

A

Myelosuppression

102
Q

Premedication of patients taking Paclitaxel

A

Steroids, diphenhydramine and an H2 blocker to decrease the incidence of allergic reactions

103
Q

Dose reduction of Paclitaxel

A

Needed in presence of hepatic dysfunction

104
Q

Uses of Paclitaxel

A

Non-small cell lung cancer
Gastroesophageal cancer
Breast cancer

105
Q

Other compounds in the same class as Paclitaxel

A

Docetaxol
Albumin bound paclitaxel
Cabazitaxel

106
Q

Use of docetaxol

A

Useful in prostate cancer when combined with prednisone

107
Q

Benefit of albumin bound paclitaxel

A

No hypersensitivity reactions and less myelosuppression and less peripheral neuropathy

108
Q

Use of cabazitaxel

A

Prostate cancer

109
Q

Class of etoposide (VP-16)

A

Plant alkaloid

Podophyllotoxin

110
Q

Macromolecular target of etoposide

A

Topoisomerase II

111
Q

MOA of etoposide

A

Complex of drug, DNA and topoisomerase II produces DNA strand breakage

112
Q

Excretion of etoposide

A

Kidneys and some in the bile

113
Q

SEs of etoposide

A

Nausea and vomiting
Hair loss
Myelosuppression (dome limiting toxicity)
Leukemogenic (total doses > 2 gm/M2 are associated with an increased incidence of treatment related leukemia)

114
Q

Dose limiting SE of etoposide

A

Myelosuppression

115
Q

Dose reductions of etoposide

A

Patients with abnormal kidney and hepatic function

116
Q

Uses of etoposide

A

Testicular cancer
Small cell lung cancer
Lymphomas

Chemotherapy Viruses (5 decks)

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