2016 - Childress - Individualized Chemotherapy Flashcards
Which chemo drugs cause direct injury to DNA?
Antimetabolites
Platinums
Alkylating agents
Anthracyclines
Antitumor antibiotics
Which chemo drugs cause indirect DNA damage? (interaction with a protein or etc)
Antimetabolites
Taxanes
Vinca alkaloids
Anthracyclines
Top I/II inhibitors
Hydroxyurea
What is Therapeutic Index (TI)?
Dose required to produce a given probability of toxicity/dose required to give a definted level of anti-tumor efficacy
Which enzyme is deficient in 23% of cats that makes them sensitive to 5-FU?
DPD (dihydropyrimidine dehydrogenase)
The enzyme needed to breakdown 5-FU
Deficiency in which enzyme in cats make them susceptible to azathioprine?
TPMT (thiopurine methyltransferase)
Deficiency in which enzyme in humans can make them sensitive to irinotecan?
UGT-1A1 (UDP-glucoronosyl transferase 1A1)
Which protein does ABCB1(MDR1) gene produce? Which mutation is common in dogs? and why is it important?
ABCB1-1delta mutation
ABCB1 encodes P-glycoprotein, a membrane associated drug efflux pump which limits intracellular/interstitial accumulation of substrate drugs
Which sites P-glycoprotein are expressed more in?
Blood-tissue barriers: BBB, testis, placenta
Luminal excretory structures: intestine, biliary epithelium, renal tubular epithelium
Some tumors
Which chemo drugs are P-glycoprotein substrates?
Anthracyclines - DOX, daunorubicin, epirubicin (Streptomyces peucetius)
Vinca alkaloids - VCR, VBL, vinorelbin (Vinca rosea)
Taxanes - paclitaxel, docetaxel (Taxus brevifolia)
Epipodophyllotoxins - etoposide, teniposide (Podophyllum pelatum)
Actinomycin-D (Streptomyces spp.)
Small molecule inhibitors - imatinib, sunitinib (Streptomyces staurosporeus)
Which breeds have high prevalence of ABCB1-1delta mutation?
Herding breeds:
Collie, English shepherd, McNab, Australian shepherd, Shetland sheepdog, Old English sheepdog, Border collie, White GSDs, Longhaired whippet, Silken windhound
What type of mutation is ABCB1-1delta mutation?
4 base pair deletion -> frame shift mutation -> premature stop codon
If a purebred dog that does not have a herding breed lineage is very sensitive to chemo, could it be because of ABCB1-1delta mutation?
NO
Based on Gustafson et al’s PK model on ABCB1-1delta muted dogs:
Is plasmal PK different in wt/wt and mut/mut dogs?
What would be most probably the dose-limiting side effect in these dogs?
What is the equipotent dose in mut/mut dogs to avoid these side effects?
Which other organ was expsed more in mut/mut dogs?
No
GI side effects, 3X DOX exposure to GI in mut/mut vs wt/wt
Reduce DOX dose to 10.7 mg/m2 in mut/mut doags
Liver, 65% greater exposure in liver
How should we dose dogs with ABCB1-1delta mutations?
No clinically validated standard
Avoid substrate drugs in mutants
Emperical dose reduction:
20-25% wt/mut; 50% in mut/mut, CAUTIOUS (5-10%) dose escalation if tolerated
Prophylactic supprotive care
Which physiologic variables scale directly with BSA?
Basal metabolic rate
Blood volume
GFR
