Tanzawa Yoshikazu, Tsuchiya Hiroyuki, Shirai Toshiharu, Nishida Hideji, Hayashi Katsuhiro, Takeuchi Akihiko, Kawahara Masami, Tomita Katsuro
Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
J Orthop Sci. 2011 Jan;16(1):77-84. doi: 10.1007/s00776-011-0045-3. Epub 2011 Mar 1.
Several reports suggest diffusion of anticancer agents from bone cement may suppress tumor growth. New drug delivery systems have been developed that incorporate anticancer drugs into calcium phosphate cement (CPC) to maintain high concentrations of anticancer drugs at local sites. We investigated whether CPC implants containing anticancer drugs and caffeine, which enhance the cytocidal effect of anticancer drugs, would enhance their antitumor effects on rat osteosarcomas (SOSN2 cells).
We calculated the release of cisplatin (CDDP) and caffeine from the CPC and bone cement. The following CPCs were prepared: CPC-only, CPC containing caffeine, CPC containing cisplatin, and CPC containing cisplatin and caffeine. We performed cell growth inhibition assays on SOSN2 cells using culture media previously used to incubate each CPC. We transplanted SOSN2 cells into the tibias of rats, excised the tumor 3 days after transplantation, implanted each CPC and observed subsequent tumor growth.
The in vitro sustained-release test demonstrated greater amounts and more persistent release of CDDP and caffeine from CPC than from bone cement and also showed CPC could release the majority of its loaded CDDP and caffeine. Culture media containing CDDP and caffeine inhibited in vitro proliferation of SOSN2 cells, and this inhibitory effect was greater than the inhibition resulting from CDDP alone. Experiments with an in vivo rat model demonstrated greater tumor growth inhibition with CPC containing CDDP and caffeine than with CPC containing CDDP alone.
The study results suggest CPC containing CDDP and caffeine potentiate antitumor effects and may be effective as a local chemotherapeutic method of treating malignant bone tumors.
多项报告表明，抗癌药物从骨水泥中扩散可能会抑制肿瘤生长。已经开发出了新的药物递送系统，即将抗癌药物掺入磷酸钙骨水泥（CPC）中，以在局部部位维持高浓度的抗癌药物。我们研究了含有抗癌药物和咖啡因（可增强抗癌药物的细胞杀伤作用）的CPC植入物是否会增强其对大鼠骨肉瘤（SOSN2细胞）的抗肿瘤作用。
我们计算了顺铂（CDDP）和咖啡因从CPC和骨水泥中的释放量。制备了以下几种CPC：仅含CPC、含咖啡因的CPC、含顺铂的CPC以及含顺铂和咖啡因的CPC。我们使用先前用于孵育每种CPC的培养基对SOSN2细胞进行了细胞生长抑制试验。我们将SOSN2细胞移植到大鼠胫骨中，移植后3天切除肿瘤，植入每种CPC并观察随后的肿瘤生长情况。
体外缓释试验表明，与骨水泥相比，CPC中CDDP和咖啡因的释放量更大且更持久，并且还表明CPC可以释放其负载的大部分CDDP和咖啡因。含有CDDP和咖啡因的培养基抑制了SOSN2细胞的体外增殖，并且这种抑制作用大于单独使用CDDP所产生的抑制作用。体内大鼠模型实验表明，含CDDP和咖啡因的CPC比仅含CDDP的CPC对肿瘤生长的抑制作用更大。
研究结果表明，含CDDP和咖啡因的CPC可增强抗肿瘤作用，可能作为治疗恶性骨肿瘤的局部化疗方法有效。
