Enhancement of Uv‐induced Skin Carcinogenesis by Azathioprine: Role of Photochemical Sensitisation

Abstract

The phototoxicity of various drugs (chlorpromazine (CPZ), metronidazole (MET), 8‐methoxypsoralen (8‐MOP), azathioprine (AZA) and the azathioprine metabolites, 6‐mercaptopurine (6‐MP), methylnitrothio‐imidazole (MNTI), methylnitroimidazole (MNI)) was determined in hairless (Skh‐hrl) mice exposed to a light source with broad emission (290–700 nm). Chlorpromazine, MET, 8‐MOP, AZA, MNI and 6‐MP were phototoxic, as determined by the oedematous response of skin, at doses comparable to those used clinically. The effects of long‐term drug therapy and UV radiation on skin carcinogenesis were then determined. Chlorpromazine and MET, and to a lesser extent AZA, MNTI and 6‐MP, enhanced photocarcinogen‐esis. In each case, both the tumour yield and the proportion of malignant:benign skin tumours were increased. The results of this study imply that prolonged treatment of mice with low‐level phototoxins predisposes to photocarcinogenesis.

Azathioprine in dermatology: The past, the present, and the future

“…51,[273][274][275][276] Laboratory data suggest that ultraviolet light and azathioprine may be synergistic and increase the risk of skin carcinomas. 277,278 Patients on higher doses and longer durations of azathioprine have been shown to have an increased risk of skin cancer, particularly squamous cell carcinoma. 279,280 Aggressive squamous cell carcinoma has been reported in dermatology patients with type 1 skin and greater than 4 years of azathioprine therapy.…”

Anti-Rejection Drug Treatment Increases Basal Cell Carcinoma Burden in Ptch1+/- Mice

“…In our model, enhancement of BCC formation occurred in the absence of UV exposure, suggesting that continued UV is not essential for drug-enhanced BCC formation and that the effects of the ARD in this model were at a post-initiation stage of BCC development. A small number of publications have reported that ARD can enhance experimental mouse (mostly hairless) squamous cell photocarcinogenesis but the reported enhancement is far less impressive than is the increased incidence of SCC observed in human OTR (Koranda et al, 1975;Nathanson et al, 1976;Daynes et al, 1979;Reeve et al, 1985;Kelly et al, 1987Kelly et al, , 1989. These reported studies used UV photocarcinogenesis and mostly used mutant hairless mice, in which UV radiation primarily causes papillomas and carcinomas of the squamous cell lineage.…”

Are patients with inflammatory eye disease treated with systemic immunosuppressive therapy at increased risk of malignancy?

“…Heart and renal transplant recipients are at an increased risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with some studies quantifying the risk as 250 and 65 times higher than the general population, respectively [2,36]. Two theories have been proposed to explain this association including (1) solar-induced mutations coupled with immunosuppression reduces tumour surveillance [37] and (2) metabolites from certain IS agents such as AZA appear phototoxic and thus increase the skin's sensitivity to ultraviolet light damage [38]. Previous studies indicate that although solar radiation may be a major contributor of skin carcinogenesis, one increasingly important risk factor is the host's immune status [6,39,40].…”