Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors

Abstract

Purpose: CXC chemokine ligand 10 (CXCL10) is a potent inhibitor of angiogenesis.We wonder whether the combination of CXCL10 with cisplatin would improve the therapeutic antitumor efficacy. Experiment Design: We evaluated the antitumor activity of the combination therapy in the immunocompetent C57BL/6 and BALB/c mice bearing LL/2 Lewis lung cancer and CT26 colon adenocarcinoma , respectively. Mice were treated with either CXCL10 s.c. at 25 Mg per kg per day once daily for 30 days, cisplatin cycled twice (5 mg/kg i.p. on days 14 and 21 after the initiation of CXCL10), or both agents together. Tumor volume and survival time were observed. Antiangiogenesis of CXCL10 in vivo were determined by alginate capsule models and CD31 immunohistochemistry. Histologic analysis and assessment of apoptotic cells were also conducted in tumor tissues. Results: CXCL10 + cisplatin reduced tumor growth in LL/2 and CT26 tumor model, respectively, more effectively, although cisplatin or CXCL10 individually resulted in suppression of tumor growth and improved survival time of tumor-bearing mice. CXCL10 successfully inhibited angiogenesis as assessed by alginate model and CD31 (P < 0.05). Histologic analysis of tumors exhibited that CXCL10 in combination with cisplatin led to the increased rate of apoptosis, tumor necrosis, and elevated lymphocyte infiltration. Conclusions: Our data suggest that the combination of CXCL10, a well-tolerated angiogenesis inhibitor, with cisplatin can enhance the antitumor activity. The present findings may be of importance to the further exploration of the potential application of this combined approach in the treatment of lung and colon carcinoma.

Evaluation of CXCL10 as a novel serum marker for predicting liver metastasis and prognosis in colorectal cancer

“…Although the antimalignancy activities of local CXCL10 expression were determined in several tumor systems, only a limited number of studies, primarily murine models, analyzed the role of CXCL10 in CRC (13)(14)(15)(16)(17). Moreover, we believe that the clinicopathological significance of CXCL10 has not been fully studied in clinical serum samples of CRC.…”

Cancer Microenvironment and Cancer Vaccine

“…It servers as a multi-functional component in the microvironment, actively participating in the regulation of different biological behaviour of cancer such as carcinogenesis [12,13], metastasis [14,15], and therapy resistance [16,17]. CAF constitutes a heterogenous population of cells from different origins such as normal fibroblast [18,19], endothelial cells [20], mesenchymal cell [21], or epithelial cells [22].…”

“…The cancer vaccine, no matter in the form of protein, DNA, or genetically modified whole cell vaccine, targeting important factors including Tie2 [55], Endoglin [11], EGFR [12] (Fig. 5), PDGF [13], or CXC10 [14], all achieved anti-angiogeneic and antitumor effects. Both cellular and humoral immune responses were involved, depending on the specific molecules, and even more critically, the route of administration and component of the vaccine.…”

Introduction

“…Antiangiogenic therapy, such as the use of TKIs that block the VEGFR, aims to disrupt existing capillaries that feed a tumor and prevent new vessels from forming around it [28]. Studies using VEGF pathway inhibitors as monotherapy have demonstrated low objective response rates; antiangiogenic agents can be effective in inhibiting tumor growth, but in most studies they do not destroy tumors [29], although this can be overcome by combining angiogenesis inhibitors with cytotoxic therapies [30][31][32][33][34][35]. Bevacizumab, a monoclonal antibody targeting VEGF that was recently approved for the treatment of colorectal cancer, extended survival in a recent clinical trial when used in combination with chemotherapy for selected patients with NSCLC with nonsquamous histology and lacking brain metastases or bleeding [36].…”

“…There is also evidence that many commonly used chemotherapeutic drugs have antiangiogenic activity [38]; the question is how best to administer these agents to use both their cytotoxic and antiangiogenic properties [39,40]. Angiogenesis inhibitors are most effective with a dose schedule that maintains a constant concentration in the circulation [40], and the use of gene therapy to deliver antiangiogenesis genes has shown promise in preclinical models [35,41,42].…”