Mitsunaga S, Clapper M, Litwin S, Watts P, Bauer B, Klein-Szanto A J
Fox Chase Cancer Center, Department of Pathology, Philadelphia, Pennsylvania 19111, USA.
J Cell Biochem Suppl. 1997;28-29:81-9.
The effect of the chemopreventive agent D,L-alpha-difluoromethylornithine (DFMO) on the incidence of skin squamous cell carcinoma was studied in SENCAR mice treated weekly with topical applications of benzo(a)pyrene (B(a)P) (0.15 mmol, 2 x /week) on the dorsal skin. Animals were randomized to receive either chow or chow supplemented with DFMO (1 g/1 kg) and studied at 10, 15, 20, 25, and 30 weeks of B(a)P treatment. Morphometric analyses at each timepoint evaluated the epidermal thickness (ET) and the number of epidermal nucleated layers (NL). The ET increased from 12-17 microns as early as 10 weeks after B(a)P treatment, reaching 22 microns at 20 weeks, and 27 microns at 25 weeks (130% increase). The NL also increased markedly. A relatively modest increase in ET was observed in animals treated with B(a)P and DFMO (16% at 15 weeks, 53% at 20 weeks, and 85% at 25 weeks) as compared to controls. The relative increase in NL showed a similar pattern. Although extensive epidermal hyperplasia was seen early, clear-cut focal premalignant lesions were not identifiable before week 20 of B(a)P treatment. At 20 weeks, the most frequently noted focal premalignant lesions in carcinogen-treated animals (without DFMO) were moderate dysplasias. At 25 and 30 weeks, a large increase was seen in the incidence of more advanced dysplastic lesions and invasive carcinomas. In the group treated with B(a)P and DFMO, a marked reduction in the number of carcinomas was observed at 25 and 30 weeks. At 25 weeks, DFMO reduced tumor yield from 5.8 to 3.2 carcinomas per mouse. At 30 weeks, the reduction was from 13.1 to 5.7 carcinomas per mouse (57% reduction). Collectively, these data emphasize the strong chemopreventive effect of DFMO against tumors in the mouse skin complete carcinogenesis model, as indicated by the reduction of overall skin tumor incidence and the decreased epidermal hyperplasia in DFMO-treated animals. Morphometrically defined increases in ET and NL can be used as early biomarkers of DFMO chemoprevention in mouse skin tumorigenesis.
在每周于背部皮肤局部涂抹苯并(a)芘（B(a)P，0.15 mmol，每周2次）的SENCAR小鼠中，研究了化学预防剂D,L-α-二氟甲基鸟氨酸（DFMO）对皮肤鳞状细胞癌发病率的影响。将动物随机分为两组，一组给予普通饲料，另一组给予添加了DFMO（1 g/1 kg）的饲料，并在B(a)P处理的第10、15、20、25和30周进行研究。在每个时间点进行形态计量分析，评估表皮厚度（ET）和表皮有核层数（NL）。早在B(a)P处理10周后，ET就从12 - 17微米增加，在20周时达到22微米，在25周时达到27微米（增加了130%）。NL也显著增加。与对照组相比，在接受B(a)P和DFMO处理的动物中观察到ET的相对增加较为适度（15周时增加16%，20周时增加53%，25周时增加85%）。NL的相对增加呈现出类似的模式。尽管早期可见广泛的表皮增生，但在B(a)P处理20周之前未发现明确的局灶性癌前病变。在20周时，致癌物处理组（未使用DFMO）中最常见的局灶性癌前病变是中度发育异常。在25周和30周时，更高级别发育异常病变和浸润性癌的发病率大幅增加。在接受B(a)P和DFMO处理的组中，在25周和30周时观察到癌的数量显著减少。在25周时，DFMO使每只小鼠的肿瘤产量从5.8个癌减少到3.2个。在30周时，减少幅度从每只小鼠13.1个癌降至5.7个（减少了57%）。总体而言，这些数据强调了DFMO在小鼠皮肤完全致癌模型中对肿瘤具有强大的化学预防作用，这表现为DFMO处理动物的总体皮肤肿瘤发病率降低以及表皮增生减少。形态计量学定义的ET和NL增加可作为小鼠皮肤肿瘤发生中DFMO化学预防的早期生物标志物。
