Cancer Drugs Flashcards
(128 cards)
1
Q
List the subclasses of alkylating agents.
A
Nitrogen Mustards Alkylsulfonates Nitrosoureas (Below drugs are partly aklylators) Platinum Drugs (cisplatin) Dacarbazine (a triazene) Procarbazine (a hydrazine)
2
Q
List the Nitrogen Mustards. (and their common clinical uses)
A
Cyclophosphamide (non-Hodgkin’s Lymphoma, breast/ovarian cancers, neuroblastoma)
Mechlorethamine (Hodgkin’s lymphoma)
3
Q
What is the MOA of Nitrogen Mustards?
A
Alkylate DNA at N7 guanine –> prevent DNA replication through abnormal base pairing, breakage through guanine excision, cross-linking
4
Q
What are the mechanisms of resistance to Nitrogen Mustards ?
A
DNA repair, decreased drug permeability, and production of trapping agents such as thiols
5
Q
LIst toxicities of Cyclophosphamide.
A
Expected: GI distress, myelosuppression, alopecia
Other: renal/urotoxic (hemorrhagic cystitis), cardiac dysfunciton, pulmonary toxicity, increased ADH secretion
6
Q
List toxicities of Mechlorethamine.
A
GI distress, myelosuppression, alopecia, sterility
*also it is a VESICANT (causes blistering)
7
Q
What drug is taken with Mesna? Why?
A
Cyclophosphamide to protect against acrolein (breakdown product during hepatic CYP450 mediated biotransformation of drug)
8
Q
What is the consequence of acrolein?
A
causes renal (tubular acidosis, proximal damage, malreabsorption) and urotoxicity/bladder tumors (hemorrhagic cystits*)
9
Q
What are the methods of resistance to cyclophosphamide?
A
DNA repair enzyme upregulation
10
Q
What type of cells are affected by nitrogen mustard?
A
affects replicating cells (late G1-S)
11
Q
List the alkyl sulfonates. What is its major us?
A
Busulfan (in chronic myelogenous leukemia)
12
Q
What are the adverse effects of busulfan?
A
adrenal insufficiency, lung fibrosis, skin pigmentation
13
Q
What is the ROA of nitrogen mustards?
A
oral, if available
14
Q
What is the MOA of Busulfan?
A
Alkylate DNA, prevent DNA replication
15
Q
What is the ROA of busulfan? How does it act in aqueous solution?
A
oral or IV
Spontaneous hydrolysis in aqueous solution –> liberates active methane sulfates
16
Q
List examples of Nitrosoureas.
A
Carmustine (BCNU)
Lomustine (CCNU)
17
Q
What is the MOA of Carmustine (BCNU)?
A
Alkylate DNA, prevent replication/ decomposition products carbomolyate proteins: inhibit DNA repair
18
Q
True or false Nitrosoureas can access BBB.
A
True- lipophilic, nonionized–> crosses BBB (so useful for brain tumors)
19
Q
List the platinum drugs? What are their common uses?
A
cisplatin (testicular carcinoma or cancer of bladder, lung, and ovary)
carboplatin (same as cisplatin)
oxaliplatin (advanced colon cancer)
20
Q
What is the MOA of Lomustine (CCNU)?
A
Alkylate DNA, producing intra- or inter-strand crosslinks that prevent DNA replication
21
Q
What are the toxicities located with cisplatin?
A
GI distress, mild hematoxicity, nephrotoxic and neurotoxic (peripheral neutopathy and acoustic nerve damage)
22
Q
What are the toxicities located with carboplatin?
A
Less renal toxicity and less peripheral neuropathy and tinnitius than Cisplatin, thrombocytopenia (greater myelosuppressant actions)
23
Q
What are the toxicities located with oxaliplatin?
A
dose limiting neurotoxicity
24
Q
What is the system of elimination with platinum drugs?
A
renal elimination
25
What toxicities are associated with Carmustine (BCNU)?
Hepatic "veno-occlusive disease", CNS (seizures, dementia), pulm fibrosis, endocrine dysfunc, thrombocytopenia, leukopenia
26
What toxicities are associated with Lomustine (CCNU)?
CNS (seizures, dementia), pulm fibrosis, endocrine dysfunc, thrombocytopenia, leukopenia
27
What system metabolizes Nitrosoureas? What is its ROA?
hepatic metabolism
| Parenteral
28
What is the toxicity associated with dacarbazine?
Alopecia, skin rash, GI distress, myelosuppression, phototoxicity, and flulike syndrome
29
What is the MOA of procarbazine?
Reactive agent that forms hydrogen peroxide, which generates free radicals and causes DNA strand scission
30
What are the toxicities associated with procarbazine?
Disulfiram-like effect, leukopenia, GI irritation, CNS dysfunction, peripheral neuropathy, skin reactions
Inhibits MAO (and other enzymes
31
What is the common use of procarbazine?
Hodgkin's lymphoma
32
What method of elimination is used for procarbazine?
hepatic metabolism
33
What is the MOA of platinum drugs?
Alkylated DNA at N7 guanine after activation in water. Produced intrastrand G-A cross-links. Interrupts replication and transcription.
34
What are methods of resistance to cisplatin?
glutathione (traps alkylating agents)
35
What platinum drug is associated with development of AML (4yr after treament)?
cisplatin
36
What platinum drug is associated with break and miscoding--> p53 activation and induction of apoptosis?
cisplatin
37
True or false carboplatin and oxaliplatin are taken ONLY orally.
FALSE: taken ONLY IV
38
What is the MOA of dacarbazine?
Metabolically activated DNA methylating agent (on O6 guanine)
39
What are mechanisms of resistance to dacarbazine?
Removal of methyl groups from O6-guanine by AGT
40
True or false: procarbazine can penetrate CSF.
TRUE!! orally active and can penetrate most tissues
41
True or false: alkylating agents are CCNS drugs.
TRUE!
42
Antimetabolites are antagonists of what compounds?
Folic acid
Purines
Pyrimidines
43
Name a folic acid antimetabolite.
Methotrexate
44
Name the purine antimetabolites.
mercaptopurine
| thioguanine
45
Name a pyramidine antimetabolites.
fluorouracil, cytarabine, gemcitabine
46
True or false: antimetabolites are CCNS drugs.
FALSE: they are CCS drugs acting primarily in the S phase of the cell cycle
47
Other than cytotoxic effects on neoplastic cells, what is another function of antimetabolites?
immunosuppressants
48
What is the MOA of methotrexate. What compound is formed that is important for its action?
inhibits dihydrofolate reductase leading to decrease in synthesis of thymidylate, purine nucleotides, and amino acids (interferes with nucleic acid and protein metabolism)
*forms polyglutamate derivatives
49
What are the mechanisms of resistance to methotrexate?
- decreased drug accumulation
- changes in drug sensitivity/activity of dihydrofolate reductase
- decreased formation of polyglutamates
50
What is the ROA of methotrexate?
oral or IV
51
Methotrexate is poorly distributed to what tissue?
CNS
52
True or false: methotrexate is metabolized by the liver.
FALSE: methotrexate is NOT metabolized and it is cleared by RENAL function
53
When taking methotrexate, what is important to do?
stay well hydrated, in order to prevent crystallization of renal tubules
54
Methotrexate is used for what cancers?
choriocarcinoma, acute leukemias, etc.
55
Methotrexate has what uses outside of cancer?
Rhematoid arthritis psoriasis
| Abortifacient in ectopic pregnancy
56
What are the toxicities associated with methotrexate?
Common: bone marrow suppression, toxic to skin and GI mucosa
| Long-term: hepatotoxicity and pulmonary infiltrates/fibrosis
57
What is "leucovorin rescue"?
administration of folinic acid in order to reduce the toxic effects of methotrexate on normal cells
58
What is the MOA of purine antimetabolites (mercaptopurine and thioguanine)?
Activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism
59
What are methods or resistance to purine antimetabolites?
decrease activity of HGPRTase (activation)
| increase activity of alkaline phosphatases (inactivation)
60
What is the DDI with allopurinol and mercaptopurine?
6-MP is metabolically converted in 1 of 3 ways, 1 of which is to thiouric acid (Allopurinol blocks this pathway and can cause drug toxicity)
61
What are the main uses for purine antimetabolites?
acute leukemias and chronic myelocytic leukemia
62
What are the toxicities associated with purine antimetabolites?
- bone marrow suppression (dose limiting)
| - hepatic dysfunction (cholestasis, jaundice, necrosis)
63
What is the MOA of 5-fluorouracil?
Inhibition of Thymidylate Synthase, DNA synthesis inhibition via "thymineless death," gets incorporated into DNA -> inhibition of synthesis & function, interferes w/ mRNA translation
64
What are resistance mechanisms against 5-fluorouracil?
decreased activation of 5-FU
Increased thymidylate synthase activity
reduced drug sensitivity to this enzyme
65
What is the ROA of fluorouracil?
IV- widely distributed, even to CSF
| topically- for some keratoses/superficial basal cell carcinomas
66
How is fluorouracil eliminated?
mainly by metabolism
67
What are the uses of fluorouracil?
bladder, breast, colon, head/neck, liver, and ovarian cancers
(also topical use)
68
What pyramidine antimetabolite is MOST specific for the S phase of the cell cycle?
cytarabine
69
What is the MOA of cytarabine?
Converted to ARA-CTP, which inhibits DNA polymerase-alpha
70
What are the resistance mechanisms against cytarabine?
decreased uptake
| decreased conversion to ARA-CTP
71
What is the MOA of gemcitabine?
converted to active diphosphate and triphosphate nucleotide forms that inhibits ribonucleotide reductase and diminished pool of DNTs required for DNA synthesis.
also can be incorporated into DNA and cause chain termination
72
What is the method of elimination of gemcitabine?
metabolism mainly
73
What is the clinical use of gemcitabine?
pancreatic cancer*
non-small cell lung cancer
bladder cancer
non-Hodgkin's lymphoma
74
What are the toxicities of gemcitabine?
neutropenia
| pulmonary toxicity
75
True or false: plant alkaloids are CCNS drugs.
FALSE: CCS drugs that act in various specific phases of the cell cycle
76
List the subtypes of plant alkaloids.
Vinca Alkaloids
Podophyllotoxins
Camptothecins
Taxanes
77
What is the phase favored by Vinca Alkaloids?
M phase
78
LIst the vinca alkaloids.
vinblastine
vincristine
vinorelbine
79
What is the MOA of Vinca Alkaloids?
Bind to beta-tubulin: prevent microtubule polymerization (and mitotic spindle formation)
80
What are mechanisms of resistance against Vinca Alkaloids?
increased efflux of drugs via membrane drug transporters
81
What is the ROA of vinca alkaloids?
parenterally (can penetrate most tissues but CSF)
82
What is the elimination mechanism of vinca alkaloids?
biliary excretion
83
What are the toxicities of vinca alkaloids?
vinblastine/vinorelbine: GI distress, alopecia, bone marrow suppression
vincristine: NO myelosuppression but DOES cause neurotoxic actions (areflexia, peripher neuropathy, paralytic ileus)
84
What is the phase favored by Podophyllotoxins?
late S to early G2 phases of cell cycle
85
LIst the Podophyllotoxins.
etoposide
| teniposide (analog)
86
What is the MOA of Podophyllotoxins?
- Form complex w/ topoisomerase II & DNA to disrupt repair of dsDNA breaks
- Inhibits mitochondrial electron transport
87
What is the ROA of Podophyllotoxins?
oral administration
88
What is the mechanism of elimination of Podophyllotoxins?
renal elimination
89
What are the toxicities associated with Podophyllotoxins?
GI irritants
Alopecia
Bone marrow suppression
90
List the camptothecins.
topotecan
| Irinotecan
91
What is the MOA of camptothecins?
Inhibit DNA topoisomerase I and damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair process
92
Which camptothecin is a prodrug that is converted to active metabolite in liver?
irinotecan
93
True or false: all camptothecins are eliminated through the renal system.
False- topotecan is eliminated renally and irinotecan is eliminated in bile and feces
94
What toxicities are associated with camptothecin?
myelosuppression and diarrhea
95
List the taxanes.
paclitaxel
| docetaxel
96
What is the MOA of taxanes?
interfere with mitotic spindle and prevent microtubule DISASSEMBLY into tubulin monomers (different than alkaloids)
97
What is the ROA of taxanes?
oral
98
What are the most common uses of taxanes?
advanced breast and ovarian cancers
99
What are the toxicities associated with paclitaxel?
neutropenia
thrombocytopenia
peripheral neuropathy
possible hypersensitivity reaction during infusion
100
What are the toxicities associated with docetaxel?
neurotoxicity
| bone marrow depression
101
List the antibiotics used in cancer treatment.
```
Doxorubicin
Daunorubucin
Bleomycin
Dactinomycin
Mitomycin
```
102
True or false: Doxorubicin and Daunorubucin are CCNS drugs?
TRUE!
103
What is the MOA of Doxorubicin and Daunorubucin?
intercalate between base pairs, inhibit topoisomerase II, and generate free radicals.
Block RNA/DNA synthesis, cause DNA strand scission, membrane disruption
104
What is the ROA and excretion mechanism of Doxorubicin and Daunorubucin?
ROA: IV
Elimination: liver metabolism and excreted in bile and urine
105
What are the toxicities associated with Doxorubicin and Daunorubucin?
CARDIOTOXICITY (possibility of arrhythmias, cardiomyopathy, CHF)
bone marrow suppression
GI distress
severe alopecia
106
What may help to alleviate the cardiotoxicity of Doxorubicin and Daunorubucin?
dexrazoxane (inhibitor of free-radical administration)
107
True or False: Bleomycin is a CCNS drug?
FALSE: it is a CCS drug active in G2 phase of cell cycle
108
What is the MOA of Bleomycin?
Glycopeptides that generate free radicals which bind to DNA and cause strand breaks--inhibiting DNA synthesis
109
What is the ROA and excretion mechanism of Bleomycin?
ROA: parenterally
Inactivated: aminopeptidases
Clearance: renal clearance
110
What are the toxicities associated with bleomycin?
```
Pulmonary dysfunction (pneumonitis, fibrosis)
Hypersensitivity (chills, fever, anaphylaxis)
Mucocutaneous reactions (blisters, alopecia, hyperkeratosis)
```
111
True or false: Dactinomycin is a CCNS drug.
TRUE
112
What is the MOA of Dactinomycin?
binds to dsDNA and inhibits DNA-dependent RNA synthesis
113
What is the ROA and excretion mechanism of Dactinomycin?
ROA: parenterally
| Elimination of both intact and metabolites through bile
114
What are the toxicities associated with Dactinomycin?
bone marrow suppression
skin reactions
GI irritation
115
True or false: Mitomycin is a CCNS drug.
TRUE
116
What is the MOA of Mitomycin?
metabolized by liver enzymes to form alkylating agent that cross-links DNA
117
What is the ROA and excretion mechanism of mitomycin?
ROA: IV
Excretion: hepatic metabolism
118
What are the toxicities associated with mitomycin?
severe myelosuppression
| Toxic to heart, liver, lung, kidney
119
True or false: anticancer drugs obey 0 order kinetics.
FALSE: they obey the log kill hypothesis (1st order kinetics)
120
What are the 4 cardinal principles of combination chemotherapy?
1) Activity
2) Different MOAs
3) No/Minimal cross-resistance
4) Different pattern of toxicity
121
What two classes would you NEVER take together due to additive neurotoxicity?
vinca alkyloids and taxanes
| cause "stocking glove syndrome"
122
What cancer drug has adverse effects on the kidney?
cisplatin
123
What can be taken BEFORE fluorouracil to make 5-FU more affective?
Leucovorin will get cells to start dividing rapidly, so more cells will be in the synthesis phase (where fluorouracil works!)
124
What can be taken with mercaptopurine to increase the toxicity of it?
allopurinol
125
What should be taken with cisplatin for cytoprotection?
amifostine
126
What drugs can be administered to protect against tumor lysis syndrome?
Allopurinol (blocks xanthine oxidase at two steps)
| Rasburicase (stimulates urate oxidase to change uric acid into allantoin
127
What is tumor lysis syndrome?
if too many tumor cells lyse at the same time, lots of cellular contents are put into the blood and are shunted to the kidney to be excreted (VERY nephrotoxic)
128
P-gp overexpression is common in tumors and causes what?
P-glycoprotein is one of the components of the BBB that renders many drugs unable to pass. If this is upregulated in tumors, it will cause drug resistance.
