Carbon-ion beam irradiation in combination with cisplatin effectively suppresses xenografted malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer. This study investigated the growth-inhibitory effects of the combination of carbon ion beam irradiation (IR) and cisplatin (CDDP) on MPM xenografts. Carbon-ion beam IR at 15 Gy effectively inhibited tumor growth and decreased the tumor volume more than 90% after 9 weeks. However, tumor regrowth was observed after 17 weeks. The combination of carbon-ion beam IR (15 Gy) and CDDP significantly suppressed tumor growth after 9 weeks, with tumor regression being observed for more than 18 weeks. In contrast, X-ray IR (30 Gy) alone or in combination with CDDP effectively suppressed tumor growth and decreased the tumor volume after 11 weeks, but tumor growth was observed after 15 weeks. Carbon-ion beam IR at 25 Gy resulted in complete tumor regression without tumor regrowth in the 20-week follow-up period. Histopathological analysis revealed that combination of carbon-ion beam IR and CDDP exerted effective cytotoxic effects on MPM xenograft tumor cells and significantly promoted tumor cell necrosis, cavitation, and fibrosis when compared with individual treatment with carbon-ion beam, X-ray IR, or CDDP. Immunohistochemical analysis revealed that the expression levels of tumor cell migration and invasion-related proteins such as CXCL12, MMP2 and MMP9 were not significantly affected upon low dose (15 Gy) carbon-ion beam IR alone or in combination with CDDP but were markedly upregulated upon treatment with CDDP alone relative to control. However, IR with a high dose (25 Gy) carbon-ion beam inhibited tumor growth without upregulating these proteins. In conclusion, the combination of IR with a low dose (15 Gy) carbon ion beam and CDDP effectively suppressed MPM tumor in vivo without significantly upregulating CXCL12, MMP2 and MMP9, suggesting that combination therapy of carbon ion beam IR and chemotherapy is a promising therapeutic strategy for MPM.

Keywords: Carbon-ion irradiation; cisplatin; mesothelioma; tumor control.

Figure 1

Tumorigenicity of MESO1 and H226 cells after transplantation into nonobese diabetic-severe immunodeficiency (NOD-SCID) mice.

Figure 2

Morphological changes in the H226 xenograft tumor after irradiation with carbon ion beam or X-ray irradiation alone or in combination with cisplatin (CDDP).

Figure 3

Irradiation with carbon ion beam or X-ray irradiation alone or in combination cisplatin (CDDP) delayed H226 xenograft tumor growth.

Figure 4

Effects of carbon ion beam or X-ray irradiation alone or in combination with cisplatin (CDDP) on histopathological features of the H226 xenograft tumor.

Figure 5

Effects of irradiation with carbon ion beam or X-ray irradiation alone or in combination with cisplatin (CDDP) on the expression levels of CXCL12, MMP2, and MMP9 in H226 xenograft tumor.

Figure 6

Feasibility study of using superconducting carbon ion beam gantry to treat malignant pleural mesothelioma. The carbon ion beam can be delivered from four coplanar beam directions for diseased lung plus one non-coplanar beam direction for interlobar pleura.