Abstract
The G-CSF is used as a therapeutic drug of the febrile neutropenia in lung cancer chemotherapy, however, there were few reports that showed the effects of combination effects of G-CSF and anticancer drugs against lung cancer. In the present study, we investigated the effects of G-CSF and the combination effects of G-CSF and cisplatin on lung cancer growth. We investigated the effect of G-CSF against the LL-2 and KLN-205 cells by MTT assay and tried to detect the G-CSF receptor by RT-PCR. Next, to analyze the G-CSF effects in vivo, we transplanted the LL-2 into C57BL/6 mice, intraperitoneally administered G-CSF (30 micro/kg/day) with or without cisplatin (5 mg/kg), measured the tumor size and analyzed pathologically by HE and immunostaining. In vitro analyses, G-CSF showed no effects in LL-2 and KLN-205 cells, and RT-PCR revealed no G-CSF receptor mRNA. In vivo analyses, G-CSF alone did not significantly suppress tumor growth. However, concurrent G-CSF administration with cisplatin significantly enhanced the tumor suppressing effect of cisplatin in early stage of tumor growth. The analysis data of vWF immunostaining indicated that the neovascularization in the peripheral region of the tumors was more enhanced in G-CSF treatment mice. ELISA assay revealed that G-CSF did not influence the serum concentration of TNF-alpha and IL-12 in tumor-bearing mice. This study suggests that concurrent (combination) administration of cisplatin with G-CSF is a safe and effective method for enhancing anticancer effects and reducing chemotherapeutic agent-induced myelosuppression.
Highlights
Cytokine granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor which enhances the proliferation and differentiation of neutrophil precursor cells [1]
To ensure that the results were due to the absence of the GCSF receptor, we investigated the G-CSF receptor mRNA in these two cell lines by reverse transcription polymerase chain reaction (RT-PCR)
The hematopoietic growth factors are widely used for neutrophil recovery during chemotherapy in solid tumors, and there were few reports whether these growth factors affect solid tumor growth and they compromise anticancer drug effects
Summary
Cytokine granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor which enhances the proliferation and differentiation of neutrophil precursor cells [1]. It stimulates a variety of responses in peripheral blood neutrophils including phagocytosis, superoxide production and chemotaxis [2]. G-CSF inhibits tumor growth in a B16-BL6 melanoma cell transplanted mice model [13]. None of these studies were conducted using concurrent administration with anticancer agents. To further elucidate the role of GCSF in tumor growth, especially in combination with anticancer drugs, we used one of the most useful clinical anticancer drug cisplatins (CDDP) [14] [15] [16] [17], whose most serious side effect is bone marrow suppression [18] [19] [20], concurrently administered with G-CSF in a transplanted lung cancer cells mouse model, and the possible mechanism responsible for the effects of G-CSF on tumor growth was studied in vitro and in vivo
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