Bahnson R R, Ratliff T L
Division of Urology, Washington University School of Medicine, St. Louis, MO 63110.
J Urol. 1988 Jun;139(6):1367-71. doi: 10.1016/s0022-5347(17)42921-1.
Previous studies have reported that alpha difluoromethylornithine (DFMO), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC), has anti-tumor activity in several tumor systems. Recently, investigations have revealed that combinations of DFMO and Interferon (IFN) are synergistic in inhibiting tumor cell growth. We tested the effects of DFMO and IFN alpha, beta alone and in combination on the growth of mouse bladder tumor (MBT-2) cells both in vitro and in vivo. MBT-2 cells were incubated for 72 hours in 96 well microtiter plates with DFMO, IFN alpha, beta and combinations of both agents and percentage inhibition was calculated. In vivo studies utilized the intravesical implantation method as well as subcutaneous implantation. DFMO was administered as a 1% solution in the drinking water. IFN alpha, beta was given bi-weekly by intravesical administration. DFMO effectively inhibited MBT-2 growth in vitro. The ID50 was 0.08 mM and peak inhibitory activity was reached at concentrations of 0.16 mM and remained constant with concentrations of up to 10 mM. IFN alpha, beta also inhibited the in vitro proliferation of MBT-2 with maximum inhibition (46%) at 2,000 U/ml. Combinations of DFMO and IFN alpha, beta showed increased anti-proliferative activity. The degree of enhancement varied with synergism, additivity, or sub-additivity at varying drug concentrations. In vivo, DFMO significantly retarded the growth of tumors implanted subcutaneously (p less than .05) and significantly delayed the outgrowth of tumors implanted intravesically (p less than .01). IFN alpha, beta alone was ineffective in vivo and produced no additive effect in vivo when used in combination with DFMO. Results of our investigation show that DFMO inhibits proliferation of MBT-2 cells in vitro and exhibits a similar effect in vivo against subcutaneous and intravesical tumor implants. IFN alpha, beta alone demonstrated anti-proliferative activity in vitro but did not affect MBT-2 growth in vivo. Although the combination of DFMO and IFN alpha, beta exhibited enhanced activity in vitro, no enhancement was observed with combination therapy in vivo.
以往的研究报道，α-二氟甲基鸟氨酸（DFMO）作为鸟氨酸脱羧酶（ODC）的一种酶激活不可逆抑制剂，在多种肿瘤系统中具有抗肿瘤活性。最近，研究发现DFMO与干扰素（IFN）联合使用在抑制肿瘤细胞生长方面具有协同作用。我们测试了DFMO和α、β干扰素单独及联合使用对小鼠膀胱肿瘤（MBT-2）细胞体外和体内生长的影响。将MBT-2细胞在96孔微量滴定板中与DFMO、α、β干扰素以及两种药物的组合孵育72小时，并计算抑制百分比。体内研究采用膀胱内植入法和皮下植入法。DFMO以1%的溶液形式加入饮用水中。α、β干扰素每两周通过膀胱内给药。DFMO在体外有效抑制MBT-2生长。半数抑制浓度（ID50）为0.08 mM，在浓度为0.16 mM时达到最大抑制活性，且在浓度高达10 mM时保持不变。α、β干扰素也抑制MBT-2的体外增殖，在2000 U/ml时最大抑制率为46%。DFMO与α、β干扰素联合使用显示出增强的抗增殖活性。增强程度随不同药物浓度下的协同、相加或次相加作用而变化。在体内，DFMO显著延缓皮下植入肿瘤的生长（p<0.05），并显著延迟膀胱内植入肿瘤的长出（p<0.01）。单独使用α、β干扰素在体内无效，与DFMO联合使用时在体内也无相加作用。我们的研究结果表明，DFMO在体外抑制MBT-2细胞增殖，在体内对皮下和膀胱内肿瘤植入物也有类似作用。单独使用α、β干扰素在体外显示出抗增殖活性，但对体内MBT-2生长无影响。尽管DFMO与α、β干扰素联合使用在体外显示出增强的活性，但在体内联合治疗时未观察到增强作用。
