Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo

Abstract

BACKGROUND: The clinical use of immunotoxins (ITs) has been hampered by hepatotoxicity, and the induction of a strong human-anti-IT response. The human-anti-IT response results in neutralisation of the immunoconjugates, rendering repetitive treatment inefficacious. METHODS: We evaluated the combination of cyclosporin A (CsA) with various Pseudomonas exotoxin A-based ITs in human breast, cervical, and prostate cancer cell lines measured by protein synthesis, cell viability, and TUNEL assay. Furthermore, expression of essential proteins were analysed by western blot. We used cervical cancer model in nude rats to evaluate the anti-metastatic effect of the combination. The anti-immunogenic response by the CsA treatment was investigated in immunocompetent rats. RESULTS: The combination of CsA with ITs caused remarkable synergistic cytotoxicity, in several cancer cell lines, characterised by protein synthesis inhibition, decreased cell viability, and an increased apoptotic index. Furthermore, the combination strongly inhibited formation of metastases in a cervical cancer model in nude rats with a statistically significant increase in median survival time of the combination-treated animals, as compared with those receiving a suboptimal dose of IT alone. Notably, we found in immunocompetent rats that the anti-IT immunoresponse elicited by repeated administration of IT was efficiently abrogated by CsA; notably the antibody responds towards the highly immunogenic PE was shown to be prevented. CONCLUSION: The combination of ITs and CsA might constitute a significant improvement in the clinical potential of systemic IT treatment of cancer patients.

Treatment with Unlabeled mAb BR96 After Radioimmunotherapy with 177Lu-DOTA-BR96 in a Syngeneic Rat Colon Carcinoma Model

“…3). The same finding was reported by Andersson et al 15 in a preclinical study of Cyclosporin A in combination with immunotoxins. The range of RAHA concentration in the different groups in the present study may be explained by the myelotoxicity, as the production of RAHA might be lower when the number of white blood cells is decreased, or by individual differences.…”

“…14 Since we use immunocompetent animals, some immunosuppressive treatment should probably be used to prevent the development of immune response to the therapeutic mouse/human chimeric antibodies. We selected and evaluated Cyclosporin A according to Andersson et al 15 To the best of our knowledge, studies on RIT with subsequent administration of unlabeled mAbs have only been conducted in xenograft models of lymphomas, and not on solid tumors or in syngeneic animal models.…”

Expression of FK506 binding protein 65 (FKBP65) is decreased in epithelial ovarian cancer cells compared to benign tumor cells and to ovarian epithelium

“…In another case of ovarian metastasis of hepatocellular carcinoma sirolimus but not tacrolimus induced a long tumor free survival [30], and in a study of hepatocellular cancer, patients treated with sirolimus experienced a longer survival than patients in the tacrolimus group [31]. Finally, cyclosporin A added to immunotoxins caused synergistic cytotoxicity and strongly inhibited formation of metastases in a cervical cancer model in nude mice [32]. Thus, decreased expression of FKBP65 correlates with malignant conversion in ovarian carcinogenesis, and immunosuppression seems to improve survival.…”

Triphenylmethyl Derivatives Enhances the Anticancer Effect of Immunotoxins

“…Both the 425.3PE and 9.2.27PE have antitumor activity in vitro and in vivo in different cancer types. 1,[3][4][5][6] We hypothesized that by combining ITs with agents that target different signaling pathways in cancer cells, enhanced cytotoxic effect of the ITs would be achieved.…”

“…ITs are taken up through endocytosis, processed within the cell, and cell death is caused by inhibition of protein synthesis through adenosine diphosphate-ribosylation of elongation factor 2 and induction of apoptosis. [1][2][3][4] Apoptosis is commonly associated with activation of caspases, inactivation of the DNA repair enzyme poly-(adenosine diphosphate-ribose) polymerase (PARP), chromatin condensation, and fragmentation of DNA. Our ITs consist of the Pseudomonas exotoxin A (PE) linked to antibodies targeting the epidermal growth factor receptor or the high molecular weight-melanoma associated antigen, the 425.3 and the 9.2.27 antibody, respectively.…”