Chen G, Teicher B A, Frei E
Dana-Farber Cancer Institute, Division of Cancer Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Cancer Biochem Biophys. 1998 Jun;16(1-2):139-55.
While cancer drug resistance has been extensively studied in cell culture, little is known about more clinically relevant in vivo resistance. The in vivo resistance of a murine mammary carcinoma EMT-6 to alkylating agents was demonstrated in the present study to be associated with multiple biochemical changes. These included an up to 1.5-fold increase in activity of phase II drug metabolizing enzymes (DMEs), such as glutathione (GSH), glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), and an up to 88% decrease of phase I DME activity [7-ethoxycumarin O-deethylase (ECOD), P450 reductase (PR)] in the resistant tumors compared with the parental tumor. Transplant of either parental or resistant tumors to mice was accompanied by a decrease of both phase I and phase II DME activity in the livers of female Balb/C mice compared with the non-tumor mice. Moreover, at the protein level, while cytochrome P450 (CYP) IIB1/2 in the liver of mouse bearing both the sensitive and the resistant tumor was significantly diminished compared to that in the liver of non-tumor control mouse in Western analysis, there was actually an increase of this protein in the liver of the host bearing either of the two resistant tumors compared to that of the sensitive tumor-bearing animal. Although this in vivo resistance phenotype is not expressed in cell culture, the profile of most of the enzyme changes in the resistant tumors remained similar in in vitro culture of the isolated tumor cells. Collectively, these results demonstrate that this in vivo alkylating agent resistance is associated with multiple changes of both phase I and phase II DMEs in the resistant tumors, and some of these, such as CYP IIB1/2 protein are further altered in the resistant tumor-bearing mouse liver, suggesting a potential role of systemic factors in this resistance phenotype.
虽然癌症耐药性已在细胞培养中得到广泛研究，但对于更具临床相关性的体内耐药性却知之甚少。本研究表明，小鼠乳腺癌EMT-6对烷化剂的体内耐药性与多种生化变化有关。这些变化包括：II期药物代谢酶（DMEs）活性增加高达1.5倍，如谷胱甘肽（GSH）、谷胱甘肽还原酶（GR）、谷胱甘肽S-转移酶（GST）、谷胱甘肽过氧化物酶（GPX）和醛脱氢酶（ALDH）；与亲代肿瘤相比，耐药肿瘤中I期DME活性[7-乙氧基香豆素O-脱乙基酶（ECOD）、P450还原酶（PR）]降低高达88%。将亲代肿瘤或耐药肿瘤移植到小鼠体内，与未患肿瘤的小鼠相比，雌性Balb/C小鼠肝脏中I期和II期DME活性均降低。此外，在蛋白质水平上，在蛋白质印迹分析中，与未患肿瘤的对照小鼠肝脏相比，携带敏感肿瘤和耐药肿瘤的小鼠肝脏中的细胞色素P450（CYP）IIB1/2均显著减少，但实际上，与携带敏感肿瘤的动物相比，携带两种耐药肿瘤之一的宿主肝脏中该蛋白有所增加。尽管这种体内耐药表型在细胞培养中未表现出来，但在分离的肿瘤细胞的体外培养中，耐药肿瘤中大多数酶变化的情况仍然相似。总体而言，这些结果表明，这种体内烷化剂耐药性与耐药肿瘤中I期和II期DMEs的多种变化有关，其中一些变化，如CYP IIB1/2蛋白，在携带耐药肿瘤的小鼠肝脏中进一步改变，提示全身因素在这种耐药表型中可能起作用。
