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
2
Q
List the bis(chloroethyl)amine drugs
A
List the bis(chloroethyl)amine drugs Cyclophosphamide
Mechlorethamine (nitrogen mustard)
Chlorambucil
Melphalan
3
Q
MOA of bis(chloroethyl)amines
A
MOA of bis(chloroethyl)amines Bifunctional alkylating agents
Preferentially alkylate the N-7 position of guanine
4
Q
List the nitrosourea drugs
A
BCNU
CCNU
5
Q
MOA of nitrosourea drugs
A
Bifunctional alkylating agents
Alkylate N-7 position of guanine
6
Q
Critical alkylation site of guanine
A
O-6 position
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
8
Q
What is resistance to nitrosureas due to
A
Constitutively high levels of a repair suicide enzyme termed an alkyltransferase
9
Q
Why were nitrosureas of particular interest?
A
Highly lipophilic and cross the BBB
-Treat glioblastoma and other brain tumors
10
Q
MOA of platinum coordination compounds
A
Bifunctional alkylating agents
Alkylation occurs primarily at the N-7 position of guanine
11
Q
General mechanisms of resistance to alkylating agents
A
- Nucleotide excision repair enzymes
- Binding of the alkylating agent to sulfur containing compounds
12
Q
Class of Cyclophosphamide
A
Bifunctional alkylating agent (oxazaphosphorine)
13
Q
Cycle specificity of Cyclophosphamide
A
CCNS
14
Q
Macromolecular target of Cyclophosphamide
A
DNA
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
16
Q
MOA of Cyclophosphamide
A
Phosphoramide mustard bifunctionally alkylates the N7 position of guanine and can form interstrand and intrastrand crosslinks
17
Q
Excretion of Cyclophosphamide
A
Metabolites are excreted in the urine
18
Q
SEs of Cyclophosphamide
A
Nausea, vomiting, hair loss, myelosuppression, hematuria Acute leukemia (mutagenic effects)
19
Q
MOA of Cyclophosphamide induced hematuria
A
Acrolein -> hematuria
20
Q
Prevention of Cyclophosphamide induced hematuria
A
- Administering the drug in the morning
- Drinking 6-8 glasses of water a day and urinating frequently
- Continuous bladder irrigation (when used in high dose)
- The use of mesna (uroprotective agent)
21
Q
Uses of Cyclophosphamide
A
Breast cancer
Non-Hodgkin’s lymphoma
22
Q
Route of administration of Cyclophosphamide
A
Oral
IV
23
Q
Compounds in the same class as Cyclophosphamide
A
Nitrogen mustard
Chlorambucil
Melphalan
24
Q
SEs of all drugs in the same class as Cyclophosphamide
A
Myelosuppression as dose limiting toxicity
25
Use of Chlorambucil and Melphalan
Orally
| Chronic treatment of chronic lymphocytic leukemia, multiple myeloma
26
Class of Ifosfamide
Alkylating agent
| Isomer of Cyclophosphamide
27
Cycle specificity of Ifosfamide
CCNS
28
Macromolecular target of Ifosfamide
DNA
29
Bioactivation of Ifosfamide
- Activated by microsomal enzymes (P450 oxidase) to 4- hydroxycyclophosphamide which is in equilibrium with aldophosphamide
- Aldophosphamide is cleaved to acrolein and phosphoramide mustard
30
MOA of Ifosfamide
DNA crosslinking
31
Excretion of Ifosfamide
Excreted via the urine
32
SEs of Ifosfamide
Myelosuppression is dose limiting
Lethargy and confusion (at high doses)
Nausea, vomiting, hair loss
High occurence of hemorrhagic cystitis
33
Dose limiting SE of Ifosfamide
Myelosuppression
34
Dosing of Ifosfamide vs. Cyclophosphamide
Ifosfamide requires much higher doses
35
Coadministered drug with Ifosfamide
MESNA (uroprotective agent)
| To prevent hemorrhagic cystitis
36
MOA of MESNA
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
37
Uses of Ifosfamide
Sarcomas
| Relapsed testicular cancer
38
Class of Temozolomide
Alkylating agent (monofunctional)
39
Cycle specificity of Temozolomide
CCNS
40
Macromolecular target of Temozolomide
DNA
41
Bioactivation of Temozolomide
Spontaneous hydrolysis to DNA reactive species
42
MOA of Temozolomide
The DNA reactive species methylates the DNA and inhibits DNA function and DNA synthesis
43
Excretion of Temozolomide
1/3 of administered dose is recovered from the urine
44
SEs of Temozolomide
Myelosuppresion (dose limiting)
| Nausea, vomiting, hair loss
45
Routes of administration of Temozolomide
Oral or IV
46
In treatment with Temozolomide what may be needed prophyactically (esp. if given for a long period of time)
Prophylaxis for pneumocystis carinii pneumonia
47
Coadministration of what is possible in treatment with Temozolomide
Radiation
48
Use of Temozolomide
Malignant brain tumors- glioblastoma
49
Class of Cisplatin
Platinum coordination compounds
| Bifunctional alkylating agent
50
Cycle specificity of Cisplatin
CCNS
51
Macromolecular target of Cisplatin
DNA
52
Bioactivation of Cisplatin
Parent compound is not active
| Solution in the presence of low chloride ion concentration, the molecule undergoes sequential aquation
53
MOA of Cisplatin
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
Protein binding of Platinum coordination compounds
Tightly bound to proteins in the plasma
55
Excretion of Cisplatin
Kidneys
56
SEs of Cisplatin (heavy metal effects)
- Intense nausea and vomiting
- *Renal toxicity is dose limiting
- Myelosuppression in
57
Dose limiting Cisplatin SE
Renal Toxicity
58
How is renal toxicity avoided in use of
| Cisplatin
- Drug is given with saline/mannitol diuresis
- Chloruresis protects the kidneys
- Hydration
59
Contraindications of
| Cisplatin
- 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
Uses of Cisplatin
```
Testicular cancer (curative)
Bladder cancer
Head and neck cancer
Ovarian cancer
Small cell and non-small cell lung cancer
```
61
Platinum coordintion compounds
Cisplatin
Carboplatin (cis-diammine-1,1-cyclobutane-dicarboxylato-platinum (II))
Oxaliplatin
62
Differences between Carboplatin and Cisplatin
- Kinetics of crosslinking (takes longer)
| - Does not have to be given with saline hydration- no renal toxicity
63
Cross resistance of Carboplatin and Cisplatin
Produces the same DNA lesions so cross-resistant
64
SEs of Carboplatin
Not renal toxic
| Myelosuppression is dose limiting
65
Excretion of Carboplatin
Excreted via the kidney
| Linear relationship between carboplatin plasma clearance and glomerular filtration rate
66
Unique feature of Carboplatin dosage
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
Calculation of Carboplatin dose
Dose (mg) = AUC X (GFR + 25)
68
Uses of Carboplatin
```
Testicular cancer
Bladder cancer
Head and neck cancer
Ovarian cancer
Small cell and non-small cell lung cancer
```
69
Class of Oxaliplatin
Third generation platinum coordination compound
70
Excretion of Oxaliplatin
Kidneys (not nephrotoxic)
71
SEs of Oxaliplatin
Myelosuppression is common but not severe
| Neurotoxicity - acute and chronic sensory
72
Dose limiting SE of Oxaliplain
Myelosuppression
73
Describe Oxaliplatin induced acute neurotoxicity
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
Clinical indication of Oxaliplatin
Significant antineoplastic activity against colorectal cancer (doubling survival in patients with metastatic colorectal cancer)
75
Describe Oxaliplatin induced chronic neurotoxicity
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
List the plant alkaloids
Vincristine
Vinblastine (periwinkle plant)
Taxol (yew tree)
Etoposide is semisynthetic
77
Cell specificity of Vincristine
CCS (M-phase)
78
Cell specificity of Vinblastine
CCS (M-phase)
79
Cell specificity of Taxol
CCS (M-phase)
80
Class of Vincristine
Plant Alkaloid, Spindle poison
81
Macromolecular target of Vincristine
Tubulin
82
MOA of Vincristine
Binds to dimeric form of tubulin and prevents polymerization of tubulin/ microtubular assembly
Causes the dissolution of mitotic spindle
83
Excretion of Vincristine
Bile
84
Dose reduction of Vincristine needed in
Patients with elevated Bilirubin
85
SEs of Vincristine
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
What SE of Vincristine is dose limiting
Neuropathy
87
Uses of Vincristine
Lymphoma
Hodgkin's disease
lymphoblastic leukemia
88
SEs of Vinblastine
Much less neurotoxic than vincristine
| Dose limiting myelosuppression
89
Use of Vinorelbine
Lung cancer and breast cancer
90
MOA of vinblastine
nhibit mitotic spindle formation (spindle poison)
91
MOA of taxol
Prevent breakdown of mitotic spindle (spindle poison)
92
Schedule of taxol and vincristine administration
Drugs act on a relatively brief phase of the cell cycle and are specific - give as continuous infusion
93
MOA of etoposide (VP-16)
Inhibits topoisomerase II and DNA strand breakage occurs
| not a spindle poison
94
Class of Paclitaxel
Plant alkaloid
95
Macromolecular target of Paclitaxel
Tubulin
96
MOA of Paclitaxel
Prevents tubulin disassembly
97
Protein binding of Paclitaxel
Tightly bound to plasma proteins
98
Excretion of Paclitaxel
Biliary system
99
Metabolism of Paclitaxel
Hepatic
100
SEs of Paclitaxel
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
Dose limiting SE of Paclitaxel
Myelosuppression
102
Premedication of patients taking Paclitaxel
Steroids, diphenhydramine and an H2 blocker to decrease the incidence of allergic reactions
103
Dose reduction of Paclitaxel
Needed in presence of hepatic dysfunction
104
Uses of Paclitaxel
Non-small cell lung cancer
Gastroesophageal cancer
Breast cancer
105
Other compounds in the same class as Paclitaxel
Docetaxol
Albumin bound paclitaxel
Cabazitaxel
106
Use of docetaxol
Useful in prostate cancer when combined with prednisone
107
Benefit of albumin bound paclitaxel
No hypersensitivity reactions and less myelosuppression and less peripheral neuropathy
108
Use of cabazitaxel
Prostate cancer
109
Class of etoposide (VP-16)
Plant alkaloid
| Podophyllotoxin
110
Macromolecular target of etoposide
Topoisomerase II
111
MOA of etoposide
Complex of drug, DNA and topoisomerase II produces DNA strand breakage
112
Excretion of etoposide
Kidneys and some in the bile
113
SEs of etoposide
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
Dose limiting SE of etoposide
Myelosuppression
115
Dose reductions of etoposide
Patients with abnormal kidney and hepatic function
116
Uses of etoposide
Testicular cancer
Small cell lung cancer
Lymphomas
