Shalinsky D R, Bischoff E D, Gregory M L, Gottardis M M, Hayes J S, Lamph W W, Heyman R A, Shirley M A, Cooke T A, Davies P J
Department of Retinoid Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
Cancer Res. 1995 Jul 15;55(14):3183-91.
Retinoids are promising agents for therapy of squamous cancers. In vitro, retinoids decrease expression of differentiation markers in head and neck squamous carcinoma cells. Little information is available on effects of retinoids on head and neck squamous carcinoma cell xenograft growth in vivo. To address this issue, head and neck squamous carcinoma cells (line 1483) were established as xenografts in nude mice. Control tumors grew rapidly with doubling times of 4-6 days to mean volumes of 1696 mm3 after 24 days. Histological analyses indicated the formation of well-differentiated squamous carcinoma cells exhibiting pronounced stratification (basal and suprabasal cells) and keratinization (keratin pearls) with abundant stroma. Cytokeratin 19 expression was restricted to the basal cell layers, and cytokeratin 4 expression was abundant in suprabasal cells. Mice were treated daily with 30 mg/kg 9-cis retinoic acid, 20 mg/kg all-trans-retinoic acid, or 60 mg/kg 13-cis retinoic acid by p.o. gavage on a schedule of 5 days/week over 4 weeks. Low micromolar (1.48-3.67 microM) and nanomolar (200-490 nM) concentrations of 9-cis retinoic acid and all-trans-retinoic acid were measured in plasmas and xenografts, respectively, 30 min after dosing. Retinoid treatment produced a marked suppression of the squamous cell differentiation of tumor cells manifest by decreased keratinization, loss of stratification, and accumulation of basal cells. This was accompanied by large decreases in the number of CK4-positive cells and concomitant increases of CK19-positive cells. REtinoic acid receptor-beta expression was also increased by 2.9-9.7-fold after chronic retinoid treatment. 9-cis retinoic acid and all-trans-retinoic acid decreased tumor volumes by 23 +/- 5 (SE) and 19 +/- 3%, respectively (P < or = 0.05); 13-cis retinoic acid was inactive. These retinoids did not decrease the rate of exponential tumor growth but increased the latent period until exponential growth began. These studies demonstrate that retinoids do not universally decrease tumor growth but profoundly suppress squamous cell differentiation in vivo in this xenograft model.
维甲酸是治疗鳞状细胞癌的有前景的药物。在体外，维甲酸可降低头颈部鳞状癌细胞中分化标志物的表达。关于维甲酸对体内头颈部鳞状癌细胞异种移植生长的影响，目前所知甚少。为解决这一问题，将头颈部鳞状癌细胞（1483系）在裸鼠中建立异种移植模型。对照肿瘤生长迅速，倍增时间为4 - 6天，24天后平均体积达1696立方毫米。组织学分析表明，形成了分化良好的鳞状癌细胞，表现出明显的分层（基底细胞和基底上层细胞）和角化（角质珠），伴有丰富的基质。细胞角蛋白19的表达局限于基底细胞层，而细胞角蛋白4在基底上层细胞中表达丰富。小鼠每周5天，连续4周经口灌胃给予30毫克/千克的9 - 顺式维甲酸、20毫克/千克的全反式维甲酸或60毫克/千克的13 - 顺式维甲酸。给药30分钟后，在血浆和异种移植瘤中分别测得低微摩尔浓度（1.48 - 3.67微摩尔）和纳摩尔浓度（200 - 490纳摩尔）的9 - 顺式维甲酸和全反式维甲酸。维甲酸治疗显著抑制了肿瘤细胞的鳞状细胞分化，表现为角化减少、分层消失和基底细胞积聚。这伴随着CK4阳性细胞数量的大幅减少以及CK19阳性细胞数量的相应增加。长期维甲酸治疗后，维甲酸受体β的表达也增加了2.9 - 9.7倍。9 - 顺式维甲酸和全反式维甲酸分别使肿瘤体积减少23±5（标准误）%和19±3%（P≤0.05）；13 - 顺式维甲酸无活性。这些维甲酸并未降低肿瘤指数生长率，但增加了直至指数生长开始的潜伏期。这些研究表明，在该异种移植模型中，维甲酸并非普遍降低肿瘤生长，但能在体内深刻抑制鳞状细胞分化。
