Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors.
Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors.
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发表时间：
1992-03
期刊：
影响因子：
11.2
通讯作者：
M. Gleave;J. Hsieh;H. Wu;A. C. Eschenbach;Leland W.K. Chung
中科院分区：
文献类型：
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作者：
M. Gleave;J. Hsieh;H. Wu;A. C. Eschenbach;Leland W.K. Chung
前列腺特异性抗原（PSA）预测前列腺癌患者肿瘤体积和分期的能力将得到改善，如果调节其产生和清除的因素得到更好的定义。然而，由于缺乏体内动物模型，无法全面了解PSA的药代动力学（产生、代谢和排泄的调节）。本研究的目的是开发一种用于评价体内PSA药代动力学的小鼠模型，并评估影响体外PSA产生的因素。选择人前列腺癌细胞系LNCaP，因为它是雄激素敏感的和PSA阳性的。尽管LNCaP细胞在皮下接种时通常是无致瘤性的，在无胸腺小鼠中，将1 × 106个LNCaP细胞与1 × 106个人骨成纤维细胞共同接种，可靠地产生PSA分泌癌。该LNCaP模型提供了肿瘤体积和血清PSA水平之间的准确相关性（r = 0.94），并证明肿瘤体积和雄激素是循环PSA水平的共同决定因素。去势后，血清PSA水平迅速下降至8倍，雄激素补充后升高至20倍，未检测到去势诱导的肿瘤细胞死亡或伴随的肿瘤体积变化。血清PSA水平增加0.24 ng/ml/mm 3的肿瘤，这是大约5倍低于人类的估计。PSA指数（PSA：肿瘤体积比）降低很可能是由于无胸腺小鼠中PSA清除速度比人体快7倍;除半衰期较短外，小鼠模型中的PSA清除似乎与人体相似，均遵循二室模型的一级动力学特征。有趣的是，在去势宿主中长时间生长（超过21天）后，LNCaP肿瘤能够适应雄激素剥夺的环境，由此LNCaP肿瘤恢复以与去势前状态相似的量分泌PSA的能力。在LNCaP细胞中，雄激素在体内和体外使PSA mRNA水平增加4倍。PSA mRNA表达也被各种生长因子改变。由雄激素和生长因子诱导的PSA产生的变化并不总是与由这些因子诱导的LNCaP细胞生长速率的变化平行，这表明PSA产生独立于细胞生长速率发生，并且可能受到各种相关因素的影响，包括激素和基质环境。该小鼠模型的观察结果表明，雄激素和肿瘤体积是血清PSA水平的独立决定因素，这意味着抗雄激素治疗后循环PSA的降低可能并不总是反映肿瘤体积的相应减少。
The ability of prostate-specific antigen (PSA) to predict tumor volume and stage in patients with prostate cancer would be improved if factors regulating its production and clearance were better defined. A thorough understanding of the pharmacokinetics (regulation of production, metabolism, and excretion) of PSA has been precluded, however, by the absence of an in vivo animal model. The purposes of this study are to develop a murine model for evaluating PSA pharmacokinetics in vivo and to assess factors that influence PSA production in vitro. The human prostate cancer cell line, LNCaP, was chosen because it is androgen sensitive and PSA positive. Although LNCaP cells are usually nontumorigenic when inoculated s.c. in athymic mice, coinoculation of 1 x 10(6) LNCaP cells with 1 x 10(6) human bone fibroblasts reliably produces PSA-secreting carcinomas. This LNCaP model provides accurate correlation between tumor volume and serum PSA levels (r = 0.94) and demonstrates that tumor volume and androgens are codeterminants of circulating PSA levels. Following castration, serum PSA levels decrease rapidly up to 8-fold and increase up to 20-fold following androgen supplementation, without detectable castration-induced tumor cell death or concomitant changes in tumor volume. Serum PSA levels increase 0.24 ng/ml/mm3 of tumor, which is approximately 5-fold less than that estimated for humans. Most likely this reduced PSA index (PSA:tumor volume ratio) results from a 7-fold faster clearance of PSA in athymic mice than in humans; other than this shorter half-life, PSA elimination in the murine model appears similar to that in humans, with both following first-order kinetics characteristic of a two-compartment model. Interestingly, following prolonged growth (greater than 21 days) in castrate hosts, LNCaP tumors are capable of adapting to an androgen-deprived environment whereby LNCaP tumors regain the ability to secrete PSA in amounts similar to the precastrate state. In LNCaP cells, androgens increase PSA mRNA levels 4-fold in vivo and in vitro. PSA mRNA expression is also altered by various growth factors. Changes in PSA production induced by androgens and growth factors do not always parallel changes in LNCaP cell growth rate induced by these factors, suggesting that PSA production occurs independently of cell growth rate and may be influenced by various interrelated factors, including hormonal and stromal milieu. Observations from this murine model suggest that androgens and tumor volume are independent determinants of serum PSA levels and imply that decreases in circulating PSA following antiandrogen therapy may not always reflect a corresponding reduction in tumor volume.