Synergistic effects of paclitaxel and gemcitabine on androgen-independent prostate cancer

Abstract

Abstract: Objective To observe the synergistic effects of paclitaxel (PA) and gemcitabine (GE) in vitro and in vivo on prostate cancer cell line PC-3. Methods Cell morphological observation, MTT assay, flow cytometry, and immunocytochemical method were used to observe the effects of 1±10^-6 mol/L, 1×10^-7 mol/L and 1×10^-8 mol/L PA and 1×10^-7 mol/L, 1×10^-8 mol/L and 1×10-9 mol/L GE on prostate cancer cell line PC-3 in vitro in a single or combined administration for 48 h. Male BALB/C-nu mice bearing PC-3 prostate cancer were treated with docetaxol and retinoic acid singly or synergistically, followed by measurement of the body weight and immunohistochemical examination of serum prostate specific antigen (PSA) and PSA expression in the implanted tumors. Results GE at the concentration of 1×10^-8 mol/L significantly enhanced the effect of PA above 1×10^-7 mol/L in inducing growth inhibition (with an inhibition rate over 50.8%±4.2%, P<0.05) and apoptosis (apoptosis rate over 22.9%±2.3%, P<0.05) of PC-3 cells and in down-regulating the expression of cyclin D1 (expression rate no higher than 9.6%±1.6%, P<0.01) in PC-3 cells. GE lowered the rate of PA-induced cell cycle arrest at G₂/M phase from 70.3%±9.7% to 38.2%±4.2%, and partially reversed the G₂/M arrest (P<0.01). Synergistic treatment of the tumor-bearing mice caused little change in the body weight, but the serum PSA (51±14 ng/ml), implanted tumor mass (3.2±0.5 g) and PSA expression in the tumors (30%±3.7%) were all decreased significantly in comparison with the control mice (21.6±1.7 g). Conclusions GE can enhance PA-induced tumor cell growth suppression and apoptosis in a synergistic manner both in vitro and in vivo, suggesting their great potential in clinical treatment of androgen-independent prostate cancer.

CLC Number:

SUN Ming¹, YANG Yu-ru¹, LI Hong¹, CHEN Yi-rong², WANG Zhi-ping², LU Yi-ping¹, WEI Qiang¹, YUE Zhong-jin². Synergistic effects of paclitaxel and gemcitabine on androgen-independent prostate cancer[J]. Journal of Southern Medical University, 2004, 24(09): 1009-1012.

References

[1] 孙明,秦大山,陈一戎.紫杉醇与泌尿系肿瘤化疗研究进展[J].临床泌尿外科杂志(Clin Urol Surg J),2002,17(2):89-92.
[2] 孙明,杨宇如,魏强.吉西他滨与泌尿男生殖系肿瘤化疗研究进展[J].国外医学·泌尿系统分册(Foreign Med Sci·Sect Urol),2004,24(1):41-5.
[3] Halder S, Chintapalli J, Croce CM. Taxol induces bcl-2 phosphorylation and death of prostate cancer cells[J]. Cancer Res, 1996, 56(5): 1253-5.
[4] Muenchen HJ, Quigley MM, Pilat MJ. The study of gemcitabine in combination with other chemotherapeutic agents as an effective treatment for prostate cancer[J]. Anticancer Res, 2000, 20(2A):735-40.
[5] DiPaola RS, Rubin E, Toppmeyer D. Gemcitabine combined with sequential paclitaxel and carboplatin in patients with urothelial cancers and other advanced malignancies[J]. Med Sci Monit, 2003, 9(2): 5-11.
[6] Jordan MA, Wendell K, Gardiner S. Mitotic block induced in hela cells by low concentrations of paclitaxel results in abnormal mitotic exit and apoptotic cell death[J]. Cancer Res, 1996, 56(4): 814-25.
[7] Ricotti L, Tesei A, De Paola F. In vitro schedule-dependent interaction between docetaxel and gemcitabine in human gastric cancer cell lines[J]. Clin Cancer Res, 2003, 9(2): 900-5.
[8] Hochhauser D, Schnieders B, Ercikan-Abali E. Effect ofcyclin D1 over expression on drug sensitivity in a human fibrosarcoma cell line[J]. J Natl Cancer Inst, 1996, 88(6): 1269-75.
[9] Panvichian R, Orth K, Pilat MJ. Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line[J]. Urology,1999, 54(5): 746-52.
[10] Sadar MD, Akopian VA, Beraldi E. Characterization of a new in vivo hollow fiber model for the study of progression of prostate cancer to androgen independence[J]. Mol Cancer Ther, 2002, 1 (8): 629-37.