Uckun Fatih M, Dibirdik Ilker, Qazi Sanjive
Developmental Therapeutics Program, Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, CA, USA.
Arzneimittelforschung. 2010;60(4):218-25. doi: 10.1055/s-0031-1296276.
The current study examined the chemopreventive potential of the dual-function JAK3/EGFR tyrosine kinase inhibitor WHI-P131 (CAS 202475-60-3) in photocarcinogenesis of non-melanoma skin cancer (NMSC). Prophylactic WHI-P131 exhibited significant anti-inflammatory activity in the SKH-1 mouse model of sunburn and afforded significant protection against the inflammatory skin damage that results from UVB exposure. UVB exposure (400 mJ/cm2) increased the mutation rate of the transgene target in UVB-exposed skin of BigBlue mice by a factor of 3.7 from 8.6 x 10(-5) to 31.7 x 10(-5) but this genotoxicity was almost completely prevented by topically administered prophylactic WHI-Pl31 (1.5 mg/cm2). Chronic and repetitive exposure of vehicle-treated SKH-1 mice to 35 mJ/cm2 UVB, three times per week for 20 weeks resulted in appearance of a spectrum of lesions from actinic keratoses and squamous cell carcinoma (SCC) in situ to invasive SCC. Both the number and size of the skin lesions progressively increased over time. Notably, topical administration of WHI-P131 (1.0 mg/cm2) over the UVB target skin area on the dorsal surface 15 min before each UVB exposure significantly suppressed the photocarcinogenesis as documented by a 4-week delay in the onset of visible skin lesions, decreased total lesion volume per mouse (1.9 +/- 0.5 mm3 vs. 2.5 +/- 0.5 mm3/lesion at 20 weeks), and decreased number (1.6 +/- 0.4/mouse vs. 4.2 +/- 1.6/mouse at 20 weeks, P < 0.05) as well as smaller size of lesions and consequently a smaller total lesion volume ("skin cancer burden") (10.6 +/- 4.3 mm3 vs. 3.2 +/- 0.9 mm3 at 20 weeks, P < 0.05). These experimental findings provide unprecedented evidence that WHI-P131 may be useful as a chemopreventive agent against NMSC.
本研究检测了双功能JAK3/EGFR酪氨酸激酶抑制剂WHI-P131（CAS 202475-60-3）在非黑色素瘤皮肤癌（NMSC）光致癌作用中的化学预防潜力。预防性使用WHI-P131在SKH-1晒伤小鼠模型中表现出显著的抗炎活性，并能有效保护皮肤免受紫外线B（UVB）照射引起的炎症损伤。UVB照射（400 mJ/cm2）使BigBlue小鼠UVB照射皮肤中转基因靶点的突变率从8.6×10⁻⁵增加到31.7×10⁻⁵，增幅为3.7倍，但局部给予预防性WHI-P131（1.5 mg/cm2）几乎完全预防了这种基因毒性。用赋形剂处理的SKH-1小鼠每周3次、每次35 mJ/cm2 UVB进行慢性重复照射，持续20周，导致出现从光化性角化病、原位鳞状细胞癌（SCC）到浸润性SCC的一系列病变。皮肤病变的数量和大小随时间逐渐增加。值得注意的是，在每次UVB照射前15分钟，在UVB照射目标皮肤区域（背部）局部给予WHI-P131（1.0 mg/cm2），显著抑制了光致癌作用，表现为可见皮肤病变的出现延迟4周，每只小鼠的总病变体积减小（20周时为1.9±0.5 mm³，而未处理组为2.5±0.5 mm³/病变），病变数量减少（20周时为1.6±0.4/只小鼠，未处理组为4.2±1.6/只小鼠，P<0.05），病变尺寸变小，因此总病变体积（“皮肤癌负担”）减小（20周时为10.6±4.3 mm³，未处理组为3.2±0.9 mm³，P<0.05）。这些实验结果提供了前所未有的证据，表明WHI-P131可能作为一种预防NMSC的化学预防剂。
