Hiss Donavon C, Gabriels Gary A, Folb Peter I
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
Cancer Cell Int. 2007 Apr 18;7:5. doi: 10.1186/1475-2867-7-5.
The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The UWOV2 cell line was derived from a cystadenocarcinoma in a patient refractory to combination chemotherapy with actinomycin D, vincristine (VCR), cis-diaminedichloroplatinum (II) (CDDP) and doxorubicin (DXR). In an attempt to explain drug resistance in this cell line, we examined the effects of TM on their sensitivity to various anticancer drugs, the uptake, efflux and retention of [3H]VCR, and their ability to bind [14C]DXR and [3H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp).
TM effectively decreased the EC50 for DXR, EXR, VCR and CDDP, thus enhancing their cytotoxicity. The antibiotic also prolonged the intracellular retention time of [3H]VCR and increased the binding of both [14C]DXR and [3H]AZD to the cells.
It is concluded that the pharmacomodulatory effects of TM in these cells are mediated by global inhibition of protein and glycoprotein synthesis and synergistic interaction with antineoplastic drugs. The ability of TM to enhance the sensitivity of drug resistant tumour cells may have impact on the design and optimization of novel resistance modifiers to improve the efficacy of combination treatment of intractable neoplasms.
报道了抗生素衣霉素（TM）对多药耐药的人UWOV2卵巢癌细胞的药理调节作用。UWOV2细胞系源自一名对放线菌素D、长春新碱（VCR）、顺二氨二氯铂（II）（CDDP）和阿霉素（DXR）联合化疗耐药的患者的囊腺癌。为了解释该细胞系中的耐药性，我们研究了TM对其对各种抗癌药物敏感性的影响、[3H]VCR的摄取、外排和滞留，以及它们结合[14C]DXR和[3H]叠氮平（AZD）的能力，AZD是多药转运蛋白P-糖蛋白（Pgp）的光亲和标记物。
TM有效降低了DXR、EXR、VCR和CDDP的EC50，从而增强了它们的细胞毒性。该抗生素还延长了[3H]VCR在细胞内的滞留时间，并增加了[14C]DXR和[3H]AZD与细胞的结合。
得出结论，TM在这些细胞中的药理调节作用是通过全面抑制蛋白质和糖蛋白合成以及与抗肿瘤药物协同相互作用介导的。TM增强耐药肿瘤细胞敏感性的能力可能对新型耐药调节剂的设计和优化产生影响，以提高难治性肿瘤联合治疗的疗效。
