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Animal Models As a model for the effect of chemotherapy drugs on gonadal…
Animal Models
As a model for the effect of chemotherapy drugs on gonadal function
Types of Studies
In vivo i.e. animals; sheep or rodents
In vitro i.e. using tissues/cells
Each model and method has +/-
Need to plan model around hypothesis
Why study impact go chemo drugs on gonadal function?
more people surviving cancer; 50s 8% children survived; now 80% survive
massive medical achievement but need to protect fertility
Chow et al. (2016); healthy sibling x cancer sibling; cumulative incidence of pregnancy and live birth lower in cancer sibling
Human Studies
Xenografting
xenograft human tissue into mice; manipulate to test hypothesis--then administer chemo drug to identify effect + mechanism
Severe Combined Immunodeficient (SCID) mouse; T + B deficient; allows xenografting without tissue rejection
Oktay et al. 2000
human PFs normal maturation and respond to hormone treatment in tissue xenografts into SCID mice
showed suitable method to study gonadotoxicity
Oktay et al. 2007; xenographed 24week old human foetal ovaries (Bfs) into SCID mice
after two weeks--treated mice with single dose cyclophosphamide
12-72hrs after; removed foetal ovaries; PF counts taken; 12% reduction in PF after 12 hours treatment; 93% Bfs lost after 48hours
Cyclophosphamide high gonadotoxicity
Consistent with clinical trials
Limitations: obtaining human ovarian samples (rare; ethics)
In Vivo
Useful to address certain questions
i.e. does a woman undergo POI after treatment X?
Minisini et al (2008) [trial from 2002-2007]
recovery of menses in 145 breast cancer patients receiving chemo at different ages
younger age (<40yo) + taxmen based chemo = increased probability of recovery of menses after chemo induced amenorrhea
cyclophosphamide-based chemo + previously child-bearing women = increased probability of permanent chemo-induced amenorrhea
Co-founding factor; smoker, alcohol consumption, BMI, previous hormonal therapies also analysed
showed directly population of women response to chemo; don't tell anything cellular/mechanistic (mouse studies more beneficial)
Clinical trials lengthy; costly; animals quick way to test gonadotoxicity before human use
Mouse Studies
In Vitro
Limitations
-- need to validate in in vivo; real-life effects in vivo may differ results; interfering factors; drug is metabolised in vivo so could have different effect
Advantage
--detailed observations of mechanisms and pathways involved; full control of environment
Lopes et al. 2014; Docetaxal; chemo drug; breast + lung cancer; used perinatal mice; have PF pool; no activation of follicles; dissected ovaries post-natal day 4; cultured for 24 hours to normalise; then 24 hours in Docetaxal; reduced PF pool; damaged granulosa cells; cell death pathway unregulated; reducing number follicles to develop; POI
collect + culture ovaries in different chemo drugs
In vivo
Gücer et al. 2001; paclitaxel; effect on ovarian reserve; 5-6 week old mice; intraperitoneal injection; drug at diff concentrations or saline; removed ovaries after 7 day; time frame because mouse oestrus cycle 5 days complete full oestrus cycle; number of PF decreased as concentration of drug increased
Advantage
-- couldn't do in vitro; need to keep ovary alive to observe hormone profiles seen throughout oestrous cycle; more relevant as accurate as to what woman would go through whilst on chemo
Overall Analysis of Mouse Models
Both vivo + vitro provide insight into biological mechanisms
mouse tissue accessed quickly; manipulations easy
slightly different biological mechanisms to humans; must follow up and validate research in humans
Chemo treatment reaction varies in people; mixture of treatments often given; studying effects of chemo drugs on fertility difficult
multiple doses given; these studies only give one dose