Story M D, Mirkovic N, Hunter N, Meyn R E
Department of Experimental Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Cancer Chemother Pharmacol. 1999;44(5):367-71. doi: 10.1007/s002800050991.
Previously, we have reported that the bcl-2-expressing murine lymphoma cell line LY-ar is resistant to chemotherapy-induced apoptosis when compared to the non-bcl-2-expressing LY-as cell line. The intent of the present study was to determine whether this relationship extends to lymphomas produced from these cell lines in syngeneic mice, after treatment with the same chemotherapy agents.
LY-ar and LY-as tumors were grown in the hind legs of syngeneic mice. They were subsequently exposed to graded doses of cisplatin (CP), etoposide (VP-16), Adriamycin (ADR), cytarabine (ara-C), cyclophosphamide (CY), or camptothecin (CAM). Apoptotic bodies were scored in histological sections of tumors that had been stained with hematoxylin and eosin. Tumor growth delay was determined on tumors that were treated when they were 8 mm in diameter. Thereafter, tumor diameter was measured daily with a vernier caliper until they had grown to a maximum of 16 mm in diameter.
When transplanted into host animals, tumors derived from these two cell lines and treated in vivo with CP, VP-16, ADR, ara-C, CY, and CAM displayed apoptotic propensities similar to those seen in the same cell lines when treated in vitro. Generally, for all the drugs tested, apoptotic indices in LY-as tumors were significantly higher than in LY-ar tumors. However, tumor growth delay measurements could not be predicted with any accuracy from the apoptotic indices. For some drugs LY-ar tumors were more sensitive than LY-as tumors (CP, Vp-16, ADR, ara-C), yet LY-ar tumors were more resistant to CY.
Despite considerable interest in using apoptotic indices as predictors of treatment outcome, the data presented here suggest that these relationships are very complex. This may be especially true for chemotherapy agents for which effects in vivo are complicated by pharmacokinetics, host effects, and tumor cell heterogeneity.
此前，我们报道过，与不表达bcl-2的LY-as细胞系相比，表达bcl-2的小鼠淋巴瘤细胞系LY-ar对化疗诱导的凋亡具有抗性。本研究的目的是确定在用相同化疗药物治疗后，这种关系是否适用于同基因小鼠中由这些细胞系产生的淋巴瘤。
LY-ar和LY-as肿瘤在同基因小鼠的后腿中生长。随后，它们接受了顺铂（CP）、依托泊苷（VP-16）、阿霉素（ADR）、阿糖胞苷（ara-C）、环磷酰胺（CY）或喜树碱（CAM）的梯度剂量处理。对用苏木精和伊红染色的肿瘤组织切片中的凋亡小体进行评分。在直径为8mm时对肿瘤进行处理，测定肿瘤生长延迟情况。此后，每天用游标卡尺测量肿瘤直径，直到其直径最大达到16mm。
当移植到宿主动物体内时，源自这两种细胞系并在体内用CP、VP-16、ADR、ara-C、CY和CAM处理的肿瘤，其凋亡倾向与在体外处理时在相同细胞系中观察到的相似。一般来说，对于所有测试药物，LY-as肿瘤中的凋亡指数显著高于LY-ar肿瘤。然而，无法根据凋亡指数准确预测肿瘤生长延迟情况。对于某些药物，LY-ar肿瘤比LY-as肿瘤更敏感（CP、Vp-16、ADR、ara-C），但LY-ar肿瘤对CY更具抗性。
尽管人们对使用凋亡指数作为治疗结果的预测指标有很大兴趣，但此处给出的数据表明这些关系非常复杂。对于体内效应因药代动力学、宿主效应和肿瘤细胞异质性而变得复杂的化疗药物来说，可能尤其如此。
