German Cancer Research Center, Dept. of Medical Physics in Radiooncology, INF 280, D-69120 Heidelberg, Germany.
Int J Med Sci. 2009 Nov 18;6(6):338-47. doi: 10.7150/ijms.6.338.
If metastatic prostate cancer gets resistant to antiandrogen therapy, there are few treatment options, because prostate cancer is not very sensitive to cytostatic agents. Temozolomide (TMZ) as an orally applicable chemotherapeutic substance has been proven to be effective and well tolerated with occasional moderate toxicity especially for brain tumors and an application to prostate cancer cells seemed to be promising. Unfortunately, TMZ was inefficient in the treatment of symptomatic progressive hormone-refractory prostate cancer (HRPC). The reasons could be a low sensitivity against TMZ the short plasma half-life of TMZ, non-adapted application regimens and additionally, the aneuploid DNA content of prostate cancer cells suggesting different sensitivity against therapeutical interventions e.g. radiation therapy or chemotherapy. Considerations to improve this unsatisfying situation resulted in the realization of higher local TMZ concentrations, sufficient to kill cells regardless of intrinsic cellular sensitivity and cell DNA-index. Therefore, we reformulated the TMZ by ligation to a peptide-based carrier system called TMZ-BioShuttle for intervention. The modular-composed carrier consists of a transmembrane transporter (CPP), connected to a nuclear localization sequence (NLS) cleavably-bound, which in turn was coupled with TMZ. The NLS-sequence allows an active delivery of the TMZ into the cell nucleus after transmembrane passage of the TMZ-BioShuttle and intra-cytoplasm enzymatic cleavage and separation from the CPP. This TMZ-BioShuttle could contribute to improve therapeutic options exemplified by the hormone refractory prostate cancer. The next step was to syllogize a qualified method monitoring cell toxic effects in a high sensitivity under consideration of the ploidy status. The high-resolution flow cytometric analysis showed to be an appropriate system for a better detection and distinction of several cell populations dependent on their different DNA-indices as well as changes in proliferation of cell populations after chemotherapeutical treatment.
如果转移性前列腺癌对抗雄激素治疗产生耐药性，那么治疗选择就很少，因为前列腺癌对细胞抑制剂不太敏感。替莫唑胺（TMZ）作为一种可口服应用的化疗药物，已被证明对脑肿瘤有效且耐受性良好，偶尔会出现中度毒性，尤其适用于前列腺癌细胞，因此应用前景似乎很有希望。不幸的是，TMZ 在治疗有症状的进行性激素难治性前列腺癌（HRPC）方面效率不高。原因可能是 TMZ 对前列腺癌细胞的敏感性低、TMZ 的血浆半衰期短、应用方案不适应，此外，前列腺癌细胞的非整倍体 DNA 含量表明对治疗干预（如放射治疗或化学治疗）的敏感性不同。为了改善这种不理想的情况，我们考虑提高局部 TMZ 浓度，使其足以杀死细胞，而不论细胞内在敏感性和细胞 DNA 指数如何。因此，我们通过将 TMZ 与一种称为 TMZ-BioShuttle 的基于肽的载体系统连接起来进行干预，从而对 TMZ 进行了重新配方。该模块化载体由一个跨膜转运蛋白（CPP）组成，与一个核定位序列（NLS）连接，该 NLS 序列在 TMZ-BioShuttle 跨膜穿过并在细胞质内酶切和与 CPP 分离后，可以将 TMZ 主动递送到细胞核内。TMZ-BioShuttle 可以改善治疗选择，例如对激素难治性前列腺癌的治疗。下一步是综合一种合格的方法，在考虑倍性状态的情况下，以高灵敏度监测细胞毒性作用。高分辨率流式细胞术分析被证明是一种合适的系统，可以更好地检测和区分依赖于不同 DNA 指数的多个细胞群体，以及化疗后细胞群体增殖的变化。
