Chemo III: Antitumor drugs Flashcards Preview

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Flashcards in Chemo III: Antitumor drugs Deck (23):


Cycle cycle specific? 

What is its mechanism of action? 

What is an important characteristic factor of this drug?

Cell cycle NON-specific

Intercalates between DNA strands (sugar part of molecule binds to the phosphate backbone) --> introducing DNA protein breaks in the strand



RED in solution 



What drug in another class shares similar MOA to donamycin and doxyrubicin?

Etoposide; in relation with topoisomerases 


What is the important function of topoisomerases?


What is the role between topo I and topo II? How can drugs interfere with this process?

Topoisomerase resolve conformation and topological changes in the DNA --> release stress and supercoiling 


Topo I: introduces transient protein bridged DNA breaks in one strand of the DNA --> drug-DNA-enzyme complex, thus arrests repair at the replication fork --> single strand break

Topo II: binds both strands-introduces transient protein bridged DNS breaks in BOTH strands of the DNA --> drugs binds TPII --> ds-break 


--> total cell death


intercalating and non-intercalating topo II inhibitors and tubulin inhibitors (vinca alkaloids) are all cross-resistant due to _____


How can resistance be reversed? (2)

Have these methods proved to be beneficial?

intercalating and non-intercalating topo II inhibitors and tubulin inhibitors (vinca alkaloids) are all cross-resistant due to MULTI-DRUG RESISTANCE


P-glycoprotein is a memebrane bound efflux pump that confers resistance - giving these drugs as continuous infusions may downregulate the P-glycoprotein and reverse resistance


Giving drugs that block the efflux pump (quinine, verapamil, cyclosporine) may also reverse resistance and enhance efficacy of drug 


This has NOT made a huge impact on response rate because there are other mxns of resistance


What are some anti-cancer drugs (7 categories) and other agents (7) to which MDR cells are resistant to:


Vinca alkaloids (vinblastine, vincristine), anthracyclines (daunorubicin, doxorubicin, mitroxantrone), Epipodophyllotoxins (etoposide, teniposide), mitomycin C, actinomycin D, taxol, topotecan


Other agents:

Colchicine, puromycin, podophyllotoxin, ethidium bromoide, emetine, gramicidin D, valinomycin



Cell cycle specific?


When is dose reduction required?

AEs (4)

Dose limiting factor?

What is one extra exam that is required prior to giving therapy and why?


Intercalates into DNA and inhibits TOPO II --> DS-DNA breaks

Dose reduction: presence of jaundice, because it is excreted as a thiol adduct into bile

AEs: N/V, hair loss, stomatitis

Dose-limitaiton: myelosuppression

MUST OBTAIN AN EJECTION FRACTION --> there is cumulative toxicity as cardiomyopathy


What is cumulative toxicity?


What limitation does this have on doseage?


what is an example of cumulative toxicity?

The higher the drug you're given over time, the greater irreversible damage to an organ there will be


With repeated administratinos of drug, the damage accumulates and after a certain dose is reached, the total damage results in organ dysfunction 


--> total LIFETIME dose!


Ex) doxorubicin -- cumulative toxicity to heart; after about 550 mg/M2 total dose ~ 10% of patients will have CHF




What is schedule dependent toxicity?


what is an example?

The toxicity depends on the length of the infusion of hte dose of the drug


ex) doxorubicin

probability of developing CHF is a function of the length of the infusion of the dose -- a 96 hour infusion of drug is associated with much LESS cardiotoxicity than the same dose administered over 30 minutes


What is schedule independent cytotoxicity?



Altering the schedule of administration DOES NOT alter the ANTI-TUMOR effect of the drug


example) doxorubicin effect on tumor is NOT dependend on how the dose is administered (30 mins vs 96 hour -->same cytotoxic effect)


What cumulative toxicity does doxorubicin display?


What is the maximum life dose? 


This toxicity is seen most w/what type of schedule?


What could be done to prevent this toxicity? (2)

Doxorubicin cumulative toxicity is cardiomyopathy

Max life time dose: 400 mg/M^2

Cardiac toxicity is SCHEDULE DEPENDENT -->

shorter infusion times = more cardiac toxic than longer infusion times


You can either:

1. Pretreat with dexraxoxane; an iron chelator - thought that free radicals made by the drug complexes with iron --> cardiac tox

2. SInce anti-tumor effect is schedule INDEPENDENT (same effect whether given long or short infusion times)  and the toxicity effect is schedule DEPENDENT (greater toxicity with shorter infusion times) , increasing infusion times could decrease the cardiotox -- [free radical] won't peak and cause cardiac damage as fast



How does Irinotecan work? 


What is its indication?



Cell cycle NON-specific

Irinotecan is a topoisomerase I inhibitor


Parent compound: CPT 11 (some activity) --> carboxylesterase converts to 7-ethyl-10-hydroxycamptothecin (SN38) --> active compound hat produces single strand breaks


Colon cancer (second line to cisplatin)



What is its dose limiting factor?

AEs (6)..are there specific treatments that may help alleviate?

When is dose reduction necessary?

What is significant about its metabolism and possible effects with certain disease?

Dose-limiting factor: myelosuppression

AEs: N/V, hair loss, stomatitis, early cholinergic diarrhea (tx atropine), late secretory diarrhea (tx imodium + hydration)

Dose reduction with w/jaundice (significant hepatic metabolism)


UGTIAI is responsible for the clearance by glucuronidation of drug and bilirubin

genetic polymorphisms in the UGT1A1 promoter that lead to enz underexpression --> impairment of bilirubin metabolism via reduced glucuronidation (GILBERTS syndrome) -->irinotecan toxicity and cause severe myelosuppression/neutropenia




how does it function?

What's its indication?

Damages DNA, mxn UNKNOWN - free radical damage to DNA --> single and DS breaks...bleomycin-iron fomr 

Cell cycle SPECIFIC (G2-M phase)



FOR: part of BET treatment for testicular cancer; hodgkins


When is a dose reduction indicated for bleomycin?


AEs (2)

Dose limiting?

Cumulative toxicty?

Dose reduction necessary in pt with renal insufficience since 50% of the drug is excreted in the urine


AEs- associated with lung and skin

Hyperpigmentation of vein if given periphery (gets better with time) due to there being bleomycin hydrolase in the liver and kidney that inactivase the drug but this enzyme NOT at lungs and skin!

Lung - SOB, cough, interstitial fibrosis, restricting ventilation

Dose-limiting: pulmonary toxicity (CUMULATIVE TOXICITY)


What is important to monitor when giving bleomycin? 


What should be avoided when administrating bleomycin?


Obtain diffuse capacity of carbon-monoxide DLCO at base line, before administration of therapy


AVOID admin of high oxygen concentration, could lead to ARDS

couldn't detox lungs, and high amounts of oxygen could lead to increas amounts of free radicals 


How can hormonal agent be useful in the treatmetn of some cancers?

Prednisone/steroid could be useful in treatmetn of cancers that are dependent on hormones for their growth. 



breast cancer - 60% dependent on estrogen or progesteron and 60^ of women w/ BCA will respond to estrogen therapy

Prostate cancer- in most patients, depedent on adrogen; 80% of men will produce favorable response to hormonal tx



What could prednisone be useful for? 


What are some side effects of using prednison?

Myeloproliferative or lymphoproliferative disorders such as multiple myeloma, hodgkin's disease, non-hodgkin's lymphoma, some forms of leukemia


WT gain, hypertension, edema, carbohydrate intolerance (if borderline DM, can very likely become diabetic), suppression of pitutiary adrenal axis, weakness, euphoria, INC appetite


Whats the role of dexamethasone in chemotherapy?


Prednisone vs dexa?

Dexamethasone, used along with 5-HT3 inhibitors to prevent or ameliorate chemotherapy treatmet related nausea and vomiting


LESS mineralcorticoid activity than prednisone and is used in the treatmetn of CEREBRAL EDEMA or SPINAL CORD EDEMA due to spinal cord compression (ie-when tumor is causing a compression to the spinal cord)







What is an important measurement before administration?

oral selective estrogen receptor modulator (SERMS)

Agonist-antagonist with respect to estrogen receptors

(antagonist in cancer cells of the breast, agonist in uterine lining -- could actually lead to the proliferation of the endometrium and the development of endometrial CA of hte uterus)


Must measure estrogen receptors on the all breast CA speciments to see if pt would response to SERMS treatmetn in eithe radjucant or metastatic setting = predictive of response


Can prevent breast cancer in women at high risk (PROPHYLAXIS!)


What are the side effects of tamoxifen?

Hot flashes, thrombosis, endometrial CA, dec rate of bone loss in postmenopausal women




How do aromatase inhibitors work?




Side effects (5)

Examples of aromatase inhibitors (3)

cut down estrogen production at the adrenals and peripheral tissues

--> rapid decrease estrogen levels

very effective in estrogen receptor positive breast cancers

Aromatase inhibitors are NOT CURATIVE -- sooner or later CA will become resistance and independent of estrogen; at that point, use of other traditional chemo drugs are indicated


side effects: arthralgias, bone pain, bone loss, osteoporosis, hot flashes


Anastrozole, letrozole, exemetane 


What is the goal of prostate cancer treatment?

How  (2) and what drugs could have this effect (3)?

DEC testosterone production via androgen deprivation therapy

most prostate cancers are hormonally dependent


1. inhibit cancer of testosterone

Flutamide, bicalutamide

don't have to measure receptors


2. DEC levels of testosterone by DEC FSH and LH using 

gonadotropin releasing hormone agonist

Leuprolide acetate


Leuprolide acetate:


What could the patient experience when at the start of tx?

How could this be prevented?


General side effects: (6)

GIven intramuscularly-depot available, every 3-6 months


Initially patient could possibly experience tumor flare by initial stimulation of FSH and LH (until positive feedback --> negative)

You can pretreat with flutamide or bicalutamide prior to firs treatment, which are drugs that PREVENT cancer cells from taking up testosterone


SE: weakness, DEC libido, erectile dysfxn, loss of muscle mass, gynecomastia, change in body fat distribution