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PPOM1 Block 4 > Lecture 151 (not finished) > Flashcards

Lecture 151 (not finished) Flashcards

(111 cards)

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1
Q

What protein is essential to direct cells down a cell death (apoptosis) pathway?

A

p53

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2
Q

What seven proteins in humans coordinate in sequential steps to initiate repair of DNA mismatches?

A

DNA mismatch repair genes (MMR)

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3
Q

What 3 drug-efflux pumps commonly confer resistance to cancer agents?

A

P-glycoprotein, MRP transporter family, BCRP transporter family

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4
Q

What type of cancers are most susceptible to chemotherapy?

A

High percentage of cells synthesizing DNA, indlucing leukemia and lymphomas

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5
Q

What two drugs are most associated with secodnary leukemias?

A

Etoposide and alkylating agents

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6
Q

Metabolic complication of chemotherapy caused by breakdown products of dying cancer cells

A

Tumor lysis syndrome

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7
Q

What is the result of tumor lysis syndrome?

A

HYPERkalemia, HYPERphosphatemia, HYPERuricemia, HYPERuricosuria, HYPOcalcemia

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8
Q

What is the ultimate consequence of tumor lysis syndrome?

A

Acute renal failure

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9
Q

What class of nonselective chemotherapy drugs does cyclophosphamide belong to?

A

Alkylating agents

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10
Q

What class of nonselective chemotherapy drugs does cisplatin belong to?

A

Platinum analogs (adducting agents)

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11
Q

What class of nonselective chemotherapy drugs does carboplatin belong to?

A

Platinum analogs (adducting agents)

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12
Q

What class of nonselective chemotherapy drugs does oxaliplatin belong to?

A

Platinum analogs (adducting agents)

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13
Q

What class of nonselective chemotherapy drugs does methotrexate belong to?

A

Antifolates (antimetabolites)

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14
Q

What class of nonselective chemotherapy drugs does 5-fluorouracil belong to?

A

Fluoropyrimidines (antimetabolites)

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15
Q

What class of nonselective chemotherapy drugs does capecitabine belong to?

A

fluoropyrimidines (antimetabolites)

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16
Q

What class of nonselective chemotherapy drugs does cytarabine belong to?

A

Deoxycytidine analogs (antimetabolites)

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17
Q

What class of nonselective chemotherapy drugs does 6-mercaptopurine belong to?

A

Purine antagonists (antimetabolites)

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18
Q

What class of nonselective chemotherapy drugs does doxorubicin belong to?

A

Antitumor antibitoics

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19
Q

What class of nonselective chemotherapy drugs does vincristine belong to?

A

Vinca alkaloids (microtubule inhibitors)

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20
Q

What class of nonselective chemotherapy drugs does paclitaxel belong to?

A

Taxanes (microtubule inhibitors)

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21
Q

What class of nonselective chemotherapy drugs does docetaxel belong to?

A

Taxanes (microtubule inhibitors)

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22
Q

What class of nonselective chemotherapy drugs does irinotecan belong to?

A

Camptothecins (topoisomerase inhibitors)

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23
Q

What class of nonselective chemotherapy drugs does etoposide belong to?

A

Epipodophyllotoxins (topoisomerase inhibitors)

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24
Q

What cell cycle stage is targeted by alkylating/adducting agents?

A

Nonspecific, most vulnerable in G1 and S phase

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25
What cell cycle stage is targeted by antimetabolites?
S phase
26
What cell cycle stage is targeted by antitumor antibitoics?
Cell cycle nonspecific
27
What cell cycle stage is targeted by microtubule inhibitors?
M phase
28
What cell cycle stage is targeted by topoisomerase inhibitors?
S phase
29
What is the major site of alkylation within DNA?
N7 position of guanine
30
What is the result of alkylating agents being used as a single agent?
Resistance develops rapidly
31
What is the result of overexpression of ALDH1 in treatment with alkylating agents?
Increased metabolism to inactive forms by aldehyde dehydrogenase
32
What is the dose-limiting toxicity of alkylating agents?
Bone marrow suppression (myelosuppression)
33
"Busulfan lung"; pulmonary fibrosis is a delayed toxicity of what class of nonselective cytotoxic agents?
Alkylating agents
34
What neoplasm peaks in incidence about 4 years after therapy with alkylating agents?
Acute myeloid leukemia (AML)
35
What administration methods are used for cyclophosphamide?
IV and oral
36
Cyclophosphamide distribution
Distributes in body water
37
How is cyclophosphamide activated?
Hepatic hydroxylation by CYP2B6
38
What are the two end products of cyclophosphamide activation?
Phosphoramide mustard and acrolein
39
What enzyme inactivates aldophosphamide (cytotoxic intermediate of cyclophosphamide)?
Aldehyde dehydrogenase
40
What is the result of increased aldehyde dehydrogenase expression during cyclophosphamide treatment?
Reduced level of cytotoxic metabolites
41
What is the result of glutathione transferases in cyclophosphamide treatment?
Detoxifcation of most alkylating intermediates
42
What is notable about cyclophosphamide treapeutic uses?
Very broad spectrum, used in both solid tumors and liquid cancers in adult and pediatric patients
43
What are the non-oncologic uses of cyclophosphamide?
Autoimmune disorders
44
What is the most important drug specific toxicity of cyclophosphamide?
Hemorrhagic cystitis
45
How can hemorrhagic cystisis be mitigated in cyclophosphamide treatment?
IV mesna and hydration
46
What is a less common toxicity of cyclophosphamide?
Cardiotoxicity; arrhythmia/congestive heart failure
47
How do the platinum analogs differ in distribution patterns?
Cisplatin and oxaliplatin are highly reactive with plasma proteins, whereas carboplatin is less reactive
48
How is cisplatin metabolized?
Nonenzymatic inactivation in cell and bloodstream
49
What is significant about platinum analogs excretion?
Dose adjustment required for renal insufficiency
50
How do platinum analogs enter the cell?
Passive diffusion and Cu2 transporter (CTR1)
51
What happens to platinum analogs before they can react with DNA?
Must be aquated
52
What happens after platinum analogs are aquated?
They react with purine on DNA, forming intrastrand crosslinks
53
Which platinum analog is less dependent on cancer cell repiar mechanisms?
Oxaliplatin
54
What can platinum analogs be paired with for treatment efficacy?
Synergy with radiation
55
What resistance mechanism against platinum analogs can result in decreased uptake?
Decreased expression of CTR1 (predominate mechanism of resistance)
56
What resistance mechanism against platinum analogs can result in increased efflux?
Copper efflux transporters ATP7A and ATP7B
57
What resistance mechanism against platinum analogs can result in inactivation?
Increased intracellular levels of glutathione bind to and inactive the drugs
58
What resistance mechanism against platinum analogs can result in increased repair?
Overexpression of **nucleotide-excision repair (NER)**, mismatch repair (MMR)
59
Upregulation of MMR can cause cross-rsistance in what platinum analogs?
Cisplatin and carboplatin, but not oxaliplatin
60
What are the therapeutic uses for cisplatin?
Broad spectrum- solid tumors, lymphomas
61
What are the therapeutic uses for carboplatinn?
Broad spectrum against solid tumors
62
What are the therapeutic uses for oxaliplatin?
Advanced or refractory solid tumors, lymphomas, leukemias
63
Oxaliplatin is a first-line adjuvant treatment for ____
Stage III and advanced colorectal cancer; FOLFOX
64
What is the main dose-limiting toxicity of cisplatin?
Nephrotoxicity; dose-dependent acute renal failure
65
How can cisplatin nephrotoxicity be mitigated?
Pretreatment with vigorous IV isotonic NaCl hydration
66
What adverse effects do 100% of patients on cisplatin experience?
Vomiting
67
What is an adverse effect that is unique to cisplatin?
Ototoxicity
68
How can carboplatin's adverse effects be summarized?
Overall less severe than in cisplatin
69
What is the main dose-limiting toxicity of carboplatin?
Myelosuppression
70
What adverse effect is more likely with carboplatin than other platinum analogs?
Acute hypersensitivity reaction
71
What is the main dose-limiting toxicity of oxaliplatin?
Peripheral neuropathy | Triggered and worsened by exposure to cold
72
What delayed toxicities in common in platinum analogs?
Leukemia and pulmonary fibrosis
73
What is the result of combining platinum analogs with taxanes?
Decreased clearance of taxanes and resulting taxane toxicity
74
What is the bioavailability of methotrexate?
Oral bioavailabiltiy is dose dependent
75
MTX is a substrate of ____
P-gp
76
MTX-PG binds with high affinity to the active catalytic site of ____
DHFR
77
MTX ultimately results in the absence of what cofactor?
FH4 cofactor
78
What is the end result of MTX MOA?
MTX impairs synthesis of thymidylate and purine nucleotides
79
What are the therapeutic uses of MTX?
Solid tumors and hematopoietic neoplasms
80
What medication can be administered to "rescue" bone marrow and GI cells from toxicity caused by MTX?
Leucovorin
81
What are two non-cancer uses for MTX?
Immunosuppression and tubal ectopic pregnancy
82
Why do sulfonamines & phenytoin interact with MTX?
They displace MTX from albumin, causing toxicity
83
What is the distribution of 5-FU?
Penetrates extracellular fluid, CSF, and thrid space fluids
84
How is 5-FU activated?
Enzymatic ribosylation and phosphorylation to active nucleotides F-UMP and F-dUMP
85
What enzyme metabolizes 5-FU?
DPD
86
How is 5-FU excreted?
Partially as CO2 excreted by the lungs
87
What deficiency should be screened for before treatment with 5-FU?
DPD deficiency, can cause toxicity
88
Capecitabine is an oral prodrug of ____
5-FU
89
Where is capecitabine converted to 5-FU?
In the liver to inactive intermediates and then to 5-FU in the tumor
90
What is the mechanism of fluoropyrimidine analogs?
Inhibition of thymidylate synthase, and interference with RNA/DNA metabolism
91
The ternary complex in fluroropryimidine results in what?
"thymineless death"
92
What is significant about thymidine phosphorylase expression in fluoropyrimidine analog treatment?
Expression has been shown to be higher in tumors than normal tissue, confers selectivity
93
What results in decreased activation in relation to resistance to 5-FU?
Cancer cells do not covert 5-FU to 5-FdUMP
94
What substrate is altered to allow resistance to 5-FU?
Altered or increased thymidylate synthase levels
95
What are the therapeutic uses for 5-FU?
Broad spectrum for solid tumors and skin cancers
96
What combinations is 5-FU used in to treat colorectal cancer?
FOLFOX or FOLFIRI
97
What is the dose-limiting toxicity of capecitabine?
Diarrhea
98
What cutaneous toxicity is seen in capecitabine treatment?
Hand-Foot syndrome
99
How is cytarabine administered?
Continusous IV infusion
100
How is cytarabine excreted?
In urine as ARA-U (inactive metabolite)
101
How is cytarabine activated?
By hepatic and intracellular tumor and host kinases to active ARA-C triphosphate
102
What explains the selectivity of cytarabine?
Cytidine deanimase is higher in normla tissues than in AML or lymphoma
103
What is the overall MOA of cytarabine?
DNA polymerase inhibition
104
What does inhibition of DNA polymerase-alpha cause?
Blocks DNA synthesis
105
What does inhibition of DNA polymerase-beta cause?
Prevents DNA repair
106
Why is cytarabine a potent immunosuppressive?
Inhibits T and B lymphocyte proliferation
107
What is the primary mechanism of resistance to cytarabine?
Decreased conversion to active form by loss of deoxycytidine kinase
108
What are the therapeutic uses for cytarabine?
Liquid malignancies, absolutely no activity in solid tumors
109
What is the drug of choice for treating AML?
Cytarabine
110
What are the main toxicities of cytarabine?
Potent myelosuppression, tumor lysis syndrome
111

PPOM1 Block 4 (44 decks)

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