Chapter 18

Question 1

Name at least 3 mechs of resistance to alkylators and cisplatin. Is cross resistance common in these groups?

Answer 1

Decreased cell drug uptake
Enhanced drug efflux
Reduced drug activation
Increased drug inactivation
Increased DNA damage repair

NO

Question 2

cross resistance to chemically unrelated drugs occurs dt what mech of resistance - give example

Answer 2

enhanced drug efflux from cells - ex MDR, LRP

Question 3

name at lesat 3 mechs of resistance to tumor metabolites

Answer 3

impaired drug transport into cells
overproduction or reduced afinity of target
upreg of alternative biochemical pathways
impaired activation or increased inactivation of the drug
increased efflux

Question 4

explain the goldie coldman hypothesis

Answer 4

the probability of a tumor having at least 1 drug resistant clone is dependent on tumor size. after 6 doublings, it is almost certain that a drug resistant clone is present. implies chance for cure is higher the sooner therapy is started. also predicts better therapeutic effect when 2 equally equally effective and non-cross resistant drugs are alternated rather than given sequentially bc it minimizes the chance of a resistant clone emerging

Question 5

name at least 2 ways that epigenetic changes in cells can lead to unstable (or non-permanent) drug resistance

Answer 5

DNA methylation that alters gene expression - in the CpG islands of promoter regions causing gene silencing
Transient gene amplification
Histone acetylation

Question 6

what are the 3 processes by which drugs can enter cells?

Answer 6

passive diffusion
facilitated diffusion
active transport

Question 7

p-glycoprotein is encoded by the gene ___. p glycoprotein is a member of the superfam of membrane proteins known as adenosine-triphosphate (ATP) binding cassette (ABC) transporters. Name 2 others

Answer 7

MDR1

MRP1 (multidrug resistance protein) breast cancer resistance protein, and lung resistance protein

Question 8

name 3 drug families commonly used in vet med that tumors can be resistant to dt upregulated PGP.
Name at least 1 other commonly used drug in oncology (not chemo) that is also excreted by this pump.

Answer 8

Anthracyclines
vincas
taxanes
epipodophyllotoxins
mtx

5HT3 receptor antagonists and morphine, sestimibi

Question 9

name 2 tissue/organs that express relatively high levels of PGP normally

Answer 9

adrenals and kidney
moderate levels in lung,liver,colon,rectum

expressed in polarized way on endothelium of BBB to exclude toxins from CNS

Question 10

name 2 differences bw MDR and MRP

Answer 10

MRP confers little resistance to paclitaxel and mitoxantrone

Question 11

reduced activation of a drug is a common form of resistance to what types of chemo? name a drug that is sensitive to resistance from increased drug deactivation and explain briefly how that works

Answer 11

Antimetabolites
Increased drug deactivation is another mech such as w/ glutathione mediated detoxicifation. So increased glutathione can lead to decreased efficacy of doxo dt detox of the formed reactive intermediates and free radicals

Question 12

name a mech of resistance that occurs w/ gleevac, mtx, 5FU

Answer 12

altered drug target

Question 13

gene amplification is a mech of resistance to many different chemo agents. name 2 examples

Answer 13

MDR for (anthracyclines, vincas, taxanes, epipodophyllotoxins, mtx)

Thymidylate synthase for 5FU
DHFR for mtx

Question 14

amplification of genes can be stable or unstable. what does this mean and how do the different processes occur in cells?

Answer 14

Stable - fixed in the genome, assoc w/ chromosomal location of the gene that is amplified such as w/ homogenously staining regions

Unstable - o/s the genome such as w/ double minute chroms such that w/ cell division the extra copies may be lost

Question 15

name 2 topo I and 2 topo II inhibitors

Answer 15

I - camptothecin, topotecan, irinotecan

II - etoposide, doxo, mitoxantrone

Question 16

improvements in dna repair can lead to resistance esp dt alkylators. what is the predominant enzyme used in repair of alkylated DNA?

Answer 16

O6-alkylguanine DNA alkyltransferase

O6-methyl guanine DNA methyltransferase

Question 17

name 2 non chemo drugs that can be used to inhibit MDR and t/f increase efficacy of chemo drugs

Answer 17

verapamil and cyclosporine

Question 18

name 2 ways hypoxic regions of tumors may have increased resistance to chemo treatment

Answer 18

lower drug concentration and lower nutrition lead to lower proliferation of cells, acidity (lower pH in region) may alter cell’s ability to take up drug into cell such as w/ mito and doxo, hypoxia can lead to gene amp that leads to resistance such as DHFR

Question 19

the process of repopulation is more common w/ (RT or CHEMO)? why?

Answer 19

more common w/ chemo bc given q3w instead of daily. cells are stimulated to divide as result of tx just as w/ bm stem cells.