Cancer II Flashcards
1
Q
principles of chemotherapy
A
- use of chemical agents to kill cancer cells
- the ultimate goal of therapy is a cure (long term, disease free survival)
- if a cure is not attainable, at least palliation (attenuation of symptoms)
- chemo is given to cancer patients whose neoplasms are not amenable to surgery or radiation therapy, also used as a supplemental treatment following surgery/radiation therapy to prevent metastasis
- most chemotherapeutic agents interfere with cell proliferation and/or induce apoptosis, rapidly dividing cancer cells are more sensitive to chemo than normal cells
2
Q
cell- kill curve
A
- a given dose of drug kills a constant fraction of cells rather than a constant number of cells- first order kinetics
- cell viability decreases with increased drug concentration
- different drugs have different effects on cell viability
3
Q
log cell kill model
A
-10^10 cancer cells is detectable
A- cancer leading to death
B- surgery/radiation leading to cure
C- surgery followed by chemo eventually leading to cure
D- surgery follow by chemo that doesn’t lead to a cure but to death
4
Q
principles of combination chemo
A
- each drug used in the regimen should have individual anticancer actions
- drugs that act by different mechanisms should be considered
- the combination therapy should have additive or synergistic effects
- drugs with different (non-overlapping) dose limiting toxicities should be used
- several cycles (6-8) of treatment should be given
5
Q
advantages of combo therapy
A
- provide maximum cell killing with less toxicity
- effective against heterogeneous cell population present in tumors
- reduces the chances of development of resistant clones
6
Q
ABVD
A
-hodgkins
7
Q
MOPP
A
-hodgkins
8
Q
FEC, FAC
A
-breast cancer
9
Q
limitations of chemo
A
- drug resistance
- toxicity
10
Q
drug resistance
A
-most tumors acquire resistance after prolonged administration of drug mechanism: 1. decreased cellular uptake 2. abnormal transport of drug (rapid efflux by p-glycoprotein) 3. increased cellular inactivation 4. altered target protein 5. reduced affinity for the drug 6. enhanced repair of DNA damage
11
Q
toxicity
A
-chemo agents aimed at killing cancer cells also affect normal cells undergoing rapid proliferation common side effects: 1. neutropenia 2. thrombocytopenia 3. anemia 4. nausea/vomiting 5. stomatitis 6. alopecia 7. leukemia/myelodysplasia in long term treatment with chemotherapeutic agents
12
Q
anticancer drugs
A
- seven classes based on their mechanisms of action
1. alkylating agents
2. antimetabolites
3. DNA intercalating agents
4. MT inhibitors
5. topoisomerase inhibitors
6. hormones and their antagonists
7. miscellaneous agents- antibodies, kinase inhibitors
13
Q
alkylating agents
A
- compounds with the ability to transfer and alkyl group to DNA
- promote cross linking of DNA strands resulting in DNA damage
- cell cycle non-specific agents- act on proliferating and resting cells
- evolved from chemical warfare agents (mustard gas)
- first agents used clinically to treat cancer patients- goodman and gilman initiated studies of nitrogen mustards in patients with lymphoma in 1942
- add alkyl group to N7 of guanine- cross links form
14
Q
toxicities of alkylating agents
A
- dose related bone marrow suppression (neutropenia, thrombocytopenia, anemia)
- mucosal tox (oral and GI ulceration)
- N/V
- toxic effects on male and female repro
- highly carcinogenic-increased risk of secondary leukemia
15
Q
specific alkylating agents
A
- nitrogen mustards
- nitrosoureas
- triazenes
- platinum analogs
16
Q
nitrogen mustards
A
- alkylating
- mechlorethamine, cyclophosphamide, ifosafide
17
Q
nitrosoureas
A
- alkylating
- carmustine, lomustine
18
Q
triazenes
A
- alkylating
- dacarbazine, temozolomide
19
Q
platinum analogs
A
- alkylating
- cisplatin, carboplatin, oxaliplatin
20
Q
mechlorethamine
A
- alkylating nitrogen mustard
- most reactive
- first clinically used N mustard, used in combo MOPP
21
Q
cyclophosphamide/ ifosfamide
A
-alkylating N mustard
-very broad clinical spectrum, component of many combo regimes (CHOP, CMF, FAC, FEC)
-used for trt of non-hodgkins lymphoma, breast, lung, and ovarian cancers
-ifosamide is used for trt of sarcoma and testicular carcinoma
-tox:
N/V, myelosuppression
-hemorrhagic cystitis- due to accumulation of toxic drug metabolite acrolein
-pro drug- must be converted to active metabolites by cytochrome p450
22
Q
carmustine/ lomustine
A
- alkylating nitrosoureas
- highly lipophilic, used for trt of meningeal leukemias and brain tumores
- severe N/V
- profound myelosuppression
- renal tox
- pulm fibrosis
23
Q
dacarbazine/ temozolomide
A
- alkylating triazenes
- pro drugs, mono-alkylators
- darcarbazine is a component of ABVD regimen use for trt of hodgkins disease
- temozolomide has shown activity against malignant glioma
- N/V, myelosuppression
- flu like sx
24
Q
cisplatin, carboplatin, oxaliplatin
A
- alkylating platinum analogs
- inorganic platinum derivatives, covalently bind to nucleophilic sites on DNA (N7 of G); form intrastrand and interstrand cross links
25
cisplatin
- wide range of neoplasms- testicular, ovarian, cervical, bladder
- myelosuppression, nephrotox (dose limiting) (renal tubular damage and necrosis), ototox, severe N/V
26
carboplatin
- ovarian cancer
| - less toxic and less reactive, thrombocytopenia is dose-limiting
27
oxaliplatin
- in combo with 5-FU for gastric and colorectal
| - unique tox- cold induced acute peripheral neuropathy
28
antimetabolites
- structural analogs of endogenous folates, purines, or pyrimidines
- inhibit enzymes required for nt synthesis or compete with endogenous nt in DNA or RNA syn
- act specfically in the S phase- cell cycle specific
29
specific antimetabolites
1. folate analogs
2. pyrimidine analogs
3. purine analogs
30
folate analogs
antimetabolites
| -methotrexate, pemetrexed
31
pyrimidine analogs
antimetabolites
- 5 fluorouracil
- cytarabine
- gemcitabine
32
purine analogs
antimetabolite
| -6 mercaptopurine
33
methotrexate
- antimetabolite- folate analog
- most widely used antimetabolite in cancer chemo
- produced first striking remissions of leukemia (1948)
- produced first cure of a solid tumor (choricarcinoma, 1963)
- inhibits dihydrofolate reductase
- effective for childhood ALL, choriocarcinoma, osteosarcoma, breast cancer, head and neck cancer
- usually given orally, intrathecally for meningeal leukemia
- tox- bone marrow (myelosuppression), GI, renal- can crystallize in urine
- hepatotox- fibrosis/cirrhosis
- defective oogenesis or spermatogenesis and can lead to abortion
34
methotrexate mechanism of action
- stops DHFR
| - can't convert folate to tetrahydrofolate- no thymidine or purine synthesis
35
pemetrexed
- multitargeted folate analog
- inhibits DHFR and thymidylate synthetase
- trt of non-small cell lung cancer and mesothelioma
36
leucovorin
- can rescue normal cells from methotrexate damage after cancer cells have been killed
- it is a reduced folinic acid, so you need a reduced carrier, which cancer cells have less of
- malignant cells are therefore killed selectively
37
5-fluorouracil
- pyrimidine analog, antimetabolite
- pro-drug, enzymatically converted into 5-FdUMP and 5-FdUTP
- dUMP inhibits thymidylate synthetase, no thymidine
- dUTP incorporated into RNA by RNA polymerase and interferes with its function
38
5-FU 2
-must be given IV due to rapid metabolic degradation in the gut and liver
-used as a component of combo regimens for treatment of breast, colorectal, gastric, head and neck, cervical and pancreatic cancers
-used topically for basal cell carcinomas
tox:
-anorexia and nausea
-mucosal ulcerations, stomatitis and diarrhea
-thrombocytopenia and anemia
-hand foot syndrom-erythema, sensitivity to the palms and soles
-cardiac tox- acute chest pain
39
cytarabine
- AraC- pyrimidine analog/ antimetabolite
- analog of 2- deoxycytidine (natural ribose is replaced with D-arabinose)
- converted to Ara-CMP by deoxycytidine kinase
- Ara-CMP converted to Ara-CTP, which competes with dCTP for incorporation into DNA by DNA pol
- when incorporated into DNA, inhibits DNA syn
- trt of AML, also useful for ALL and blast phase CML
- severe myelosuppression
- GI tract tox
40
gemcitabine
- pyrimidine analog/ antimetabolite
- difluoro analog od deoxycytidine (dFdC)
- converted to active di and tri phosphate metabolites (dFdCDP, dFdCTP)
- dFdCDP inhibits ribonucleotide reductase, resulting in depletion of deoxyribonucleotides necessary for DNA syn
- dFdCTP competes with dCTP for incorporation into DNA and leads to termination of DNA synthesis
- more effective against solid tumors than cytarabine
- active throughout the cell cycle (unlike cytarabine)
- used as first line treatment for pancreatic carcinoma
- also effective against non-small cell lung cancer, ovarian, bladder, esophageal, and head and neck cancer
41
purine analogs 2
- antimetabolites
- identified by hitching and elion in the 40s as a treatment for hyperuricemia and gout
- later found useful for cancer
- 6 mercaptopurine (6-MP)
42
6MP
- pro drug- enzymatic conversion to ribonucleotide by HGPRT
- changed into TIMP- which inhibits phosphorubosylamine syn, stops IMP from going to AMP and XMP, and incorporates into RNA to stop syn
- TIMP stops first step of de novo syn of purine base
- used to maintain remission in ALL
- bone marrow suppression, hepatotox in prolonged used
- resistance from decreased expression of HGPRT and decreased drug transport
43
note about 6MP
- drug interaction with allopurinol, which some patients are on to decrease amount of uric acid
- inhibits XO- needed for breakdown of 6MP
- increases plasma 6MP levels, need to give a smaller dose
