17 and 18 Antineoplastics Flashcards
Cancer causes over how many deaths annually in the USA?
500,000 second only to heart disease
What is the % of diagnosed patients cured?
What percentage cured by chemotherapy?
What % cured by local measures?
- 50%
- 17%
- 33%
What are the 5 shortcomings mentioned of chemotherapies?
- cancer is a group of diseases
- cancers result from genetic alterations
- No foreign organism to target
- Harm to normal host
- low therapeutic indices
T-F—chemotherapeutic agents have high therapeutic indices?
False–a low index means its more toxic at lower doses
What 3 ways do conventional chemotherapeutic agents act?
inhibit metabolism (RNA synthesis)
Damage DNA
Interfere with mitotic machinery
T-F–chemotherapeutics do not attack the host cell?
False–they do
Does activation or inactivation of oncogenes overrides G_ arrest?
Activation, G1 arrest
Inactivation of tumor suppressor genes overrides what cell cycle arrest?
G2
When is the DNA replication checkpoint?
End of G2 phase
When is the restriction point checkpoint?
End of G1
What does S phase stand for?
synthetic phase, DNA replication
What is the order of the cell cycle starting from G0?
G1–>S—>G2—>M
What is the tumor cell growth fraction?
Fraction of cells not in G0
Are differentiated tumor cells responsive to chemotherapy?
not responsive they are in G0
[cycling cells are sensitive to cytotoxic drugs attacking cell cycle]
Which tumor cells are are responsive to conventional chemotherapy?
non G0
What is micro metastases derived from what does it lead to?
presumably derived from tumor stem cells, generally the ultimate cause of lethality
Is micrometastases susceptible to chemotherapeutic agents?
yes
Toxic side effects are most pronounced on what types of cells?
Noncancerous proliferating cells
- bone marrow
- intestinal epithelial cells
- oral mucosa
- gonadal cells
- hair follicles
according to the log kill hypothesis how many cells does each intervention kill?
eradicates the same percentage of tumor cells (you have to stop to take breaks to relieve the adverse effects in which the cancer cells grow again)
What are the 4 primary applications for chemotherapy?
1- metastatic/hematopoietic cancer
2- surgical adjuvant
3- lymphomas, leukemias
4- palliative/prolong life
What are the 3 major alkylating agents/classes of alkylating agents?
bischloroethyl amines, nitrosoureas, procarbazine
What drug was the nitrogen mustard that was used in mustard gas World War 1?
mechlorethamine
What less highly reactive derivative has been developed to replace mechlorethamine? What does it require?
cyclophophamide
-activation in liver or tumor tissues
Dechlorination of the bischloroethyl amines leaves what energy state?
+ state- electrophile
[this is what attacks neutrophils nitrogen in DNA bases]
T-F–cross linked guanine residues leads to less DNA damage?
False- more significant DNA damage
T-F–nitrosoureas have strong cross-resistance with other alkylating agents?
false-little, and this is why you can use multiple alkylating agents in multi drug treatment.
What alkylating agents cross-brain barrier, useful against brain tumors?
Nitrosoureas
What alkylating agents are effective against Hodgkin’s disease?
procarbazine
does Procarbazine have little or a lot of cross-resistance with other antineoplastic agents?
little cross-resistance
What alkylating agent might cause leukemia? what risk?
procarbazine, 5-10%
[it’s because alkylating agents are mutagenic so increase risk of another cancer]
What is the major anti-tumor antimetabolites?
Methotrexate
What metabolic substrate is methotrexate an analog of?
folic acid
What does methotrexate inhibit?
- dihydrofolate reductase
- blocks synthesis of DNA, RNA, and protein precursors
What does methotrexate accumulate as?
polyglutamate derivative
T-F methotrexate is G1 phase-specific?
False- s phase
What nucleic acid base does methotrexate impair?
thymidine
What are the mechanisms of resistance for methotrexate? 4
- amplification of DHFR gene
- DHFR gene mutation
- decreased uptake
- increased drug efflux
How do you rescue methotrexate? drug?
folinic acid—leucovorin
What are the 2 major purine antagonists? What phase are they specific to?
6-mercapto-purine
6-thioguanine
-S phase specific because block purine synthesis
What is a common mechanism of resistance for purine antagonists?
down regulation of HGPRT
[hypoxanthine-guanine phophoribosyl transferase-activates the antagonists]
T-F–6-thioguanine is metabolically inactivated by xanthine oxidase?
False__6-mercaptopurine
When does 6-mercaptopurine have low bioavailability?
administered with cow’s milk
What is administered to inhibit xanthine oxidase and therefore reduce uric acid accumulation? [gout]
allopurinol
What are the 2 pyrimidine antagonists?
5-FU[fluorouracil]
cytosine arabinoside [cytarabine]
What phase is fluorouracil specific to?
S phase
What is the oral prodrug of fluorouracil?
capecitabine
Review of the capecitabine metabolism–compound—>enzyme—> compound
capecitabine–>carboxylesterase—>5’-DFCR—>cytidine deaminase—> 5’DFUR—> thymidine phosphorylase—>5-FU—>dihydropyrimidine dehydrogenase—> alpha-fluoro-beta-alanine
Metabolic activation of cytarabine requires what? what is the significance of this enzyme?
deoxycytidine kinase—mutational loss of this is important mechanism of tumor cell resistance
What anti-tumor class and subclass does daunorubicin and doxorubicin fall under?
anti-tumor antibiotics–anthracyclines
How does anthracyclines work?
DNA intercalation, DNA topoisomerase II binding, DNA scission
What is the major side effect of anthracyclines?
irreversible cardiac toxicity at high doses
What is the main cytotoxic action of bleomycin? side effect?
DNA strand scission–side effect pulmonary fibrosis
does bleomycin have much myelosuppression?
No
Bleomycin is a natural product, what is the significance of that?
anaphylactic reactions—administer small test doses
What cell cycle is vinblastine specific to? how does it work?
M-phase–inhibitor of microtubule polymerization
What are the side effects of vinblastine?
acute nausea, vomiting, dose limiting bone marrow depression
how is resistance conferred to vinblastine?
tubulin gene mutations
What is the non-dose limiting bone marrow depression alternative to vinblastine?
vincristine [major use in childhood leukemia]
What is the mitotic spindle poison? how does it work?
paclitaxel-enhance tubulin polymerization which blocks microtubule disassembly
What is paclitaxel used for?
ovarian and advanced breast cancers
What are the 2 camptothecin topoisomerase inhibitors?
topotecan and irinotecan
Topoisomerase II creates how many breaks?
double-strand—which occurs in DNA replication therefore is Sphase -specific
Topoisomerase inhibitors block what when bound to topoisomerase I and DNA?
block relegation of single-strand break
What drug is a platinum coordination complex?
Cisplatin–similar to alkylating agent interacts with Ns in guanine
Is cisplatin cell cycle specific?
No
When is cisplatin often used?
ovarian and testicular cancer
What toxicity side-effects does cisplatin have?
nephrotoxicity, acoustic nerve dysfunction
What are the two main hormone-dependent cancers?
prostate and breast—[cause second most cancer deaths in each sex behind lung cancer]
Estrogen promotes development and proliferation of estrogen responsive tissues and which tumors?
estrogen responsive tumors are breast and uterine
What is the competitive inhibitor of estrogen binding to estrogen receptor? is it a selective estrogen response modulator?
tamoxifen–yes
Is tamoxifen an antagonist?
no-partial agonist
[efficacy differs in different tissues]
T-F–prophylactic tamoxifen treatment has been suggested as an effective means of breast cancer prevention in all women? T-F—it does not significantly increases life span?
false—high risk women only
True
T-F—tamoxifen therapy in postmenopausal women has been shown to reduce risks of bone fractures?
True
T-F—There is an increased risk of thrombosis/embolism but decreased risk of endometrial cancer with tamoxifen?
False—tamoxifen increased both
What is another selective estrogen response modulator?
raloxifene
What drug class does letrozole, anastrozole, and exemestane fall into?
aromatase inhibitors
[inhibits conversion of androgen to estrogen]
T_F—aromatase inhibitors effectively block estrogen production in in premenopausal women? Why?
False–postmenopause use…pre menopause women have compensatory gonadotropin and ovarian estrogen production
What drug class is more effective than tamoxifen for ER+ breast cancers or useful in tamoxifen-resistant tumors in postmenopausal women?
aromatase inhibitors
Exemestane greatly reduces risk of breast cancer in what % of high risk postmenopausal women?
75%
T-F—aromatase inhibitors enhance thrombosis? enhance uterine cancer?
False and False
Aromatase inhibitors may cause what problems?
joint pain, loss of bone density
What are the 2 anti-androgen drugs?
flutamide and leuprolide
Leuprolide is a synthetic peptide of what?
gonadotropin releasing hormone
Pulsatile delivery of leuprolide causes?
elevations of androgens in men and estrogens in women
Continuous, high dose delivery of leuprolid causes?
greatly lowers androgen levels in men and estrogen levels in women.
T-f—flutamide is an endrogen receptor agonist?
False-antagonist
[used with leuprolide to block effects of the initial pulse of androgen levels and flare of prostate cancer at start of therapy]
Why is flutamide alone ineffective against prostate cancer?
due to rapid androgen receptor mutations
Prednisone induces apoptosis in what cells?
leukemia
Does prednisone cure leukemia?
No [but useful for inducing remission in acute lymphoblastic or undifferentiated leukemia in children]
In cancers other than leukemia, what is prednisone used for?
palliative agent to reduce inflammation and nausea
What is oncogene addiction?
Tumor cell proliferation/survival apparently becomes dependent upon activated oncogenes
Targeted agents inhibit what?
function of activated oncogenes or proteins necessary for tumor cell proliferation and tumor angiogenesis
T-F—targeted agents are humanized chimeric antibodies? What does humanized mean?
True
- antigen recognition elements Fab of a mouse antibody and structural portions Fc of a human antibody
What are the two EGF receptor protein tyrosine kinase?
erlotinib and cetuximab
What are the 2 HER2 protein kinase target drugs?
lapatinib and trastuzumab
Which HER2 protein tyrosine kinase is the small molecule EGFR and HER2 kinase inhibitor in breast cancer?
Iapatinib
What HER2 antibody is humanized and used in breast cancer a lot?
trastuzumab
T-F–imatinib just got approved for chronic myelogenous leukemia?
True
What does brentuzimab vedotin do?
CD30 surface antigen–chimeric IgG conjugated to highly toxic mitotic spindle poison
Tumor cells surviving an initial chemotherapeutic intervention freq. show what?
resistance to the agents.
What are the 5 specific mechanisms of resistance? [review]
- drug uptake
- increased concentration of target enzyme
- decreased rate of metabolic drug activation
- increased rate of drug metabolism
- Increased rate of drug efflux.
Resistance to a variety of natural product anticancer drugs can result from the elaboration of ____???
nonspecific drug efflux pumps
What are the 3 rules of multi drug regimens?
- employ drugs not showing cross-resistance
- minimize side effects
- maximize anti-tumor effects [use each drug at highest possible
