A novel rat model for chemotherapy-induced alopecia

Abstract

Background: More than half of all people diagnosed with cancer receive chemotherapy, and approximately 65% of these develop chemotherapy-induced alopecia (CIA), a side-effect that can have considerable negative psychological repercussions. Currently, there are very few animal models available to study the mechanism and prevention of CIA.

Aim: To develop a clinically relevant adult rat model for CIA.

Methods: We first tested whether neonatal pigmented Long-Evans (LE) rats developed alopecia in response to the chemotherapeutic agents etoposide and cyclophosphamide. We then determined whether the rats developed CIA as adults. In the latter experiment, rat dorsal hair was clipped during the early telogen stage to synchronize the hair cycle, and starting 15 days later, the rats were treated with etoposide for 3 days.

Results: Neonatal LE pups developed CIA in response to etoposide and cyclophosphamide, similar to other murine models for CIA. Clipping of the hair shaft during early telogen resulted in synchronized anagen induction and subsequent alopecia after etoposide treatment in the clipped areas only. Hair follicles in the clipped areas had the typical chemotherapy-induced follicular dystrophy (dystrophic catagen). When the hair in the pigmented alopecic areas regrew, it had normal pigmentation.

Conclusions: A novel, pigmented adult rat model has been established for CIA. By hair-shaft clipping during early telogen, synchronized anagen entry was induced, which resulted in alopecia in response to chemotherapy. This is the first clinically relevant adult rat model for CIA, and will be a useful tool to test agents for the prevention and treatment of CIA.

Figure 1

Gross phenotype of Long-Evans rat pups treated with(b,e,h) etoposide or (c,f,i) cyclophosphamide compared with (a,d,g) their sham-treated littermates. Pictures were taken 7 days after the last treatment.

Figure 2

(a–i,i″) Gross phenotype and (a'-i') histology of dorsal skin sections from (group I) control rats and rats treated with etoposide with (group III) or without (group II) prior clipping. (a–i,i″) Hair on the dorsal skin of 21-day-old rats was either (b,d f,i,i″) removed with an electric clipper (group III) or (a,c,e,g,h) not clipped (groups I and II). (f) Small block arrows point to the boundary of partially regrown hair; the highlighted area in (i) is enlarged in (i″) to show that hair loss after etoposide treatment only occurred where hair was clipped on day 21. (a′–i′) Dorsal skin sections from rats in (a–i), shown at the same magnification (haematoxylin and eosin, original magnification × 50). (b′,d′,f′) The thicker skin in group III rats reflected more advanced anagen than (a′,c′,e′) control rats. Arrows point to the hair follicle (HF) features used to determine the stages of the HF cycle. (a″–f"). S-phase cells in the anagen hair bulb (arrowheads) (BrdU with haematoxylin counterstain, original magnification × 200).