cancer 2 Flashcards
(79 cards)
1
Q
combination chemotherapy is more
A
effective than single-drug treatment in most cancers
2
Q
what are the 5 examples of combination regimens?
A
- ABVD
- CHOP
- MOPP
- CMF
- FEC
3
Q
ABVD
A
doxyrubicin (adriamycin), bleomycin, vinblastine, decarbazine
4
Q
CHOP
A
cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone
5
Q
CMF
A
cyclophosphamide, methotrexate, 5-Fu
6
Q
FEC
A
5-FU, epirubicin, cyclophosphamide
7
Q
based on the mechanism of action, name the 7 classes of anticancer
A
- alkylating agents
- antimetabolites
- DNA intercalating agents
- microtubule inhibitors
- topoisomerase inhibitors
- hormones and their antagonist
- miscellaneous agents
8
Q
What are alkylating agents?
A
a group of compounds that have the ability to transfer an alkyl group to DNA
9
Q
alkylations promote
A
cross-linking of DNA strands resulting in DNA damage
10
Q
sulfur mustards were used
A
as chemical warfare agents in WW1
11
Q
what are some major classes of alkylating agents?
A
- cyclophosphamide
- ifosfamide
- carbustine
12
Q
what is the mechanism of action of the alkylating agents?
A
produce strong electrophiles through the formation of carbonium or ethyleneimonium ion intermediates, which form covalent linkages by alkylation of nucleophilic moieties present in DNA
13
Q
what is the major site of alkylation within DNA?
A
the N7 position of guanine
14
Q
what are the toxicities of alkylating agents?
A
- bone marrow toxicity (neutropenia, thrombocytopenia, anemia)
- mucosal toxicity - oral mucosal ulceration
- nausea and vomiting
- toxic effects on reproductive systems (amenorrhea in women, male sterility)
- increased reisk of leukemia
15
Q
what are the examples of resistance to alkylating agents?
A
- decreased permeability or uptake of the drugs
- increased rates of metabolism of the activated forms to inactive species
- enhanced activity of DNA repair pathways
- increased production of glutathione, which inactivates the alkylating agents throguh conjugation
16
Q
what are the 4 types of alkylating agents?
A
- nitrogen mustards (mechlorethamine, cyclophosphamide, and ifosfamide)
- Nitrosoureas (carmustine and lomustine)
- Triazenes (dacarbazine and temozolomide)
- Platinum analogs (cisplatin, carboplatin, and oxaliplatin)
17
Q
how do nitrogen mustards work?
A
they are bifunctional alkylating agents that undergo spontaneous conversion to active metabolites in body fluids or are enzymatic ally converted to active metabolites in the liver.
18
Q
what are cyclophosphamide and Ifosfamide?
A
- prodrugs that must be converted to active alkylating metabolites by hepatic cytochrome P450 enzymes.
- the active alkylating metabolite is phosphramide mustard.
- these drugs can taken orally and have a relatively long plasma half-life compared to other alkylating agents
19
Q
what are the therapeutic uses of cyclophosphamide?
A
- most widely used alkylating agent
- has a broad clinical spectrum
- used singly or as part of the combination regimen in the treatment of acute and chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, breast, lung and ovarian cancers
20
Q
ifosfamide is used to treat
A
sarcoma and testicular cancer
21
Q
toxicity of cyclophosphamide and ifosfamide?
A
- nausea, vomiting, myelosuppression
2. hemorrhagic cystitis
22
Q
mechanism for hemorrhagic cystitis?
A
local irritation in the bladder due to toxic drug metabolite (acrolein) in the urine
23
Q
what can be done to prevent hemorrhagic cystitis?
A
adequate hydration and administration of MENSA (sodium 2-mercaptoehtane sulfonate), which inactivates acrolein
24
Q
what are the names of Nitrosoureas?
A
Carmustine, Lomustine
25
what are the therapeutic usage of the Carmustine and Lomustine?
they are highly lipohpilic and are able to cross the blood-brain barrier --> b/c of their excellent CNS penetration --> these drugs have been used to treat brain tumors
26
what are the toxicity of Carmustine and Lomustine?
1. cause profound myelosuppression,
2. severe nausea and vomiting,
3. renal toxicity
4. pulmonary fibrosis
27
what are types of Triazenes?
Dacarbazine and Temozolomide
28
Dacarbazine is a
prodrug that requires metabolic activation by cytochromes in the liver
29
Dacarbazine is part of the combination regimen
(ABVD) used for the treatment of Hodgkin's disease, also used for malignant melanoma
30
Temozolmide has significant activity against malignant
gliomas, it is the standard agent in combination with radiation therapy
31
What are 3 Platinum analogs?
cisplatin, carboplatin, oxaliplatin
32
what are the mechanism of platinum analogs?
1. these drugs are inorganic platinum derivatives
2. although cisplatin and other platinum analogs do not form carbonium ion intermediates like other alkylaing agents (formally alkylate DNA), they covalently bind to nucleophilic sites on DNA
33
loading dose creates the conc
for therapeutic
34
loading dose =
Cp X Vd
35
platinum analog are converted to active cytotoxic forms by reacting with water to form positively charged, hydrated intermediates that can react with
DNA guanine, forming intrastand and interstand corss-link
36
Cisplatin has efficacy against a wide range of neoplasms and it is used for the treatment of
1. testicular
2. ovarian
3. cervical
4. bladder cancers
37
what is specifically approved for ovarian cancer?
carboplatin
38
what is specifically used for treating gastric and colorectal cancer?
oxaliplatin
39
what are the two important side effects of cisplatin?
1. renal toxicity
| 2. ototoxicity
40
what is special about the renal toxicity of cisplatin?
it's the renal tubular damage/necrosis and it's the dose-limiting toxicity
41
what is the toxicity of carboplatin?
myelosuppression (thrombocytopenia)
42
what are two important toxicity of oxaliplatin?
1. peripheral sensory neuropathy (cold-induced acute peripheral neuropathy)
2. neutropenia
43
what are antimetabolites?
they are structural analogs of folic acid or the purine/pyrimidine bases found in DNA
44
b/c antimetabolites inhibit DNA synthesis (S-phase),
they are considered as cell-cycle specific drugs or DNA synthesis inhibitors
45
what are the two antimetabolites that are folate analogs?
1. methotrexate
| 2. pemetrexed
46
methotrexate is the most widely used
antimetabolites in cancer therapy
47
methotrexate is
a folic acid antagonist that inhibits dihydrofolate reductase
48
what does dihydrofolate reductase do?
converts dietary folate to the tetrahydrofolate form required for thymidine and purine biosynthesis
49
methotrexate is effective in treating childhood
acute lymphoblastic leukemia (ALL) and choriocarcinoma
50
methotrexate is also a component of combination therapy regimens for
1. Burkitt's lymphoma
| 2. carcinomas of the breast, ovary, head and neck and bladder
51
MTX can not penetrate the CNS,
it is administered intrathecally for treatment of meningeal leukemia and meningeal metastases of a wide range of tumors
52
high dose MTX is used for
osteosarcoma
53
what are the significant toxicity of MTX?
1. bone marrow toxicity (myelosuppression, spontaneous hemorrhage)
2. GI toxicity (oral ulceration, stomatitis)
3. renal toxicity (high dose MTX can crystallize in the urine and cause renal damage
4. hepatotoxicity
54
what are the mechanism of resistance to MTX?
1. reduced drug uptake by neoplastic cells
2. increased production of DHFR (gene amplification)
3. decreased affinity of DHFR for MTX
55
Pemetrexed is a
multi-targeted folate analog
56
what are the examples of pyrimidine analogs?
1. 5-fluorouracil
2. cytarabine
3. gemcitabine
57
5-FU is a
pro-drug requireing enzymatic conversion (ribosylation and phosphorylation) into active metabolites (5-FdUMP) to exert its cytotoxic activity.
58
5-FdUMP inhitibs
thymidylate synthetase and prevents thymidine synthesis
59
what are the therapeutic uses of 5-FU?
5-FU is given IV b/c of its severe toxicity to the GI tract and rapid metabolic degradation in the gut and liver
60
5-FU is used as a component of combination therapy for treatment of
breast, colorectal, gastric, head and neck
61
what is the topical application of 5-FU?
basal cell carcinoma
62
what is a newer, orally effective form of 5-FU?
capectabine, a prodrug, which is converted to 5'-deoxy-5-fluorouridine
63
what is the toxicity of 5-FU?
1. anorexia and nausea
2. mucosal ulcerations
3. hand-foot syndrome erythema, sensitivity of the palms and soles can occur
64
what is an analog of 2'-deoxycytidine?
Cytarabine
65
what are the 2 significant toxicity of carmustine, lomustine (Nitrosoureas)?
1. renal toxicity
| 2. pulmonary fibrosis
66
what is 6-mercaptopurine?
purine analogs
67
what is the primary therapeutic uses of 6-mercaptopurine?
primarily to maintain remission in pts with ALL
68
what are the two mechanisms of resistance of 6-mercaptopurine?
decreased expression of HGPRT
69
what is an important drug interaction of 6-MP
allopurinal, which is used to treat hyperuricemia --> allopurinol inhibits xanthine oxidase and thereby increases plasma MP levels
70
what should be done to pts receiving allpurinol?
decrease the dose of 6-MP
71
what is 6-MP?
purine analog (pro-drug)
72
6-MP requires
enzymatic conversion to ribonucelotide by HGPRT
73
what is one of the pyrimidine analogs which is converted to Ara-CMP by deoxycytidine kinase?
Cytarabine (Ara-C)
74
what is the most important therapeutic usage of cytarabine (Ara-C)?
AML
75
what is 5-FU?
pyrimidine analog, a pro-drug which is enzymatically converted into active metabolite 5-FdUMP
76
5-FU must be given
IV due to rapid metabolic degradation in the gut and liver
77
toxicity of 5-FU?
hand foot syndrome - erythema, sensitivity to the palms and soles
78
how can the toxic effect of MTX be prevented?
by leucovorin
79
what are the two important toxicity of nitrosoureas (carmustine, lomustine)?
renal toxicity, pulmonary fibrosis
