hTERT-promoter-based tumor-specific expression of MCP-1 effectively sensitizes cervical cancer cells to a low dose of cisplatin

Abstract

Cervical cancers at advanced stages or with recurrent status are mainly treated by platinum-based chemotherapy, such as cisplatin. However, a novel strategy to reduce the minimally effective dose is required to prevent severe adverse effects that limit the effectiveness of the treatment. Monocyte chemoattractant protein-1 (MCP-1) is a subtype of chemokines that can promote monocyte/macrophage infiltration and enhance their phagocytosis at not only sites of inflammatory lesions but also of tumors. The present study applies MCP-1-based gene therapy to treat cervical cancers. To achieve tumor-specific expression of MCP-1, retroviral expression vector was constructed using the human telomerase reverse transcriptase gene (hTERT) promoter. Retroviral expression of MCP-1 into cervical cancer ME180 cells did not affect their proliferation either in vitro or in vivo. However, when combined with a suboptimal low dose of cisplatin, tumor formation was obviously reduced in clones transduced with MCP-1, but not in control clones. Histological examination revealed that a substantial number of macrophages infiltrated the tumor sites of MCP-1-transduced cells, but not of controls. These findings suggest that MCP-1 expression sensitizes cervical cancer cells to an otherwise ineffective low dose of cisplatin, possibly by inducing the migration of macrophages to eradicate tumor cells. This system may be a novel strategy for chemotherapy combined with immunogene therapy against otherwise intractable cervical cancers.

Enhanced suicide gene therapy using a tumor-specific promoter in combination with cisplatin

“…The results provide further support for the ῾indirected-activator' strategy, by which DNA damage can be used to enhance the hTerT promoter in targeted gene therapy. This hypothesis may provide a novel explanation for the satisfactory results obtained by other researchers combining cisplatin with gene therapy using the hTerT promoter (9,(33)(34)(35).…”

“…The human uterine cervical cancer cell line Hela was used, since the hTerT promoter has been applied to mediate tumorspecific expression in cervical cancer cells (9,10). Cisplatin is the standard systemic chemotherapeutic agent for cervical cancer (11).…”

Telomere and telomerase as targets for anti-cancer and regeneration therapies

“…The specific expression of telomerase hTERT in most types of tumors provides a good discrimination between cancer and normal cells [6,7] . Deletion analysis of the hTERT promoter reveals a core promoter region located approximately 200 bp upstream of the transcription start site, and is sufficient to confer its specific expression in cancer cells [71] . The property of hTERT promoter has been applied to restrict the expression of therapeutic genes in tumors.…”

“…The property of hTERT promoter has been applied to restrict the expression of therapeutic genes in tumors. The therapeutic genes utilized include apoptosis-inducing [72][73][74] , toxin-encoding [75] , chemotherapeutic sensitizer [71] , xenoantigen [76] genes, or genes used in genedirected enzyme prodrug therapy (GDEPT) [77,78] . These hTERT promoter-driven therapeutic genes were introduced into tumor cells through liposome-or virus-mediated pathways.…”

Highly specific targeting of HPV genes using ribozymes

“…The introduction of tumor-suppressive or pro-apoptotic genes such as p53 3,4 and its homologues, 5 Rb, 6 bax 7 and MCP1, 8 cell cycle inhibitors such as p21 WAF/CIP1 , 9 and more recently, antisense RNA, 10-12 siRNA 13 and ribozymes [14][15][16] against viral genes, have been found to be effective in inhibiting the growth of cervical cancer cells.…”