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.
References
[1]
Demetri, G.D. and Griffin, J.D. (1991) Granulocyte Colony-Stimulating Factor and Its Receptor. Blood, 78, 2791-2808.
[2]
Asano, S. (1991) Human Granulocyte Colony-Stimulating Factor: Its Basic Aspects and Clinical Applications. American Journal of Pediatric Hematology/Oncology, 13, 400-413. https://doi.org/10.1097/00043426-199124000-00004
[3]
Kuritzkes, D.R. (2000) Neutropenia, Neutrophil Dysfunction, and Bacterial Infection in Patients with Human Immunodeficiency Virus Disease: The Role of Granulocyte Colony-Stimulating Factor. Clinical Infectious Diseases, 30, 256-260.
https://doi.org/10.1086/313642
[4]
Banerjea, M.C. and Speer, C.P. (2002) The Current Role of Colony-Stimulating Factors in Prevention and Treatment of Neonatal Sepsis. Seminars in Neonatology, 7, 335-349. https://doi.org/10.1053/siny.2002.0116
[5]
Bohlius, J., Reiser, M., Schwarzer, G., et al. (2003) Impact of Granulocyte Colony-Stimulating Factor (CSF) and Granulocyte-Macrophage CSF in Patients with Malignant Lymphoma: A Systematic Review. British Journal of Haematology, 122, 413-423. https://doi.org/10.1046/j.1365-2141.2003.04450.x
[6]
Azoulay, E. and Delclaux, C. (2004) Is There a Place for Granulocyte Colony-Stimulating Factor in Non-Neutropenic Critically Ill Patients? Intensive Care Medicine, 30, 10-17. https://doi.org/10.1007/s00134-003-2049-8
[7]
Berliner, N., Horwitz, M. and Loughran, T.P. (2004) Congenital and Acquired Neutropenia. Hematology. American Society of Hematology. Education Program, 63-79. https://doi.org/10.1182/asheducation-2004.1.63
[8]
Berdel, W.E., Danhauser-Riedl, S., Steinhauser, G., et al. (1989) Various Human Hematopoietic Growth Factors (Interleukin-3, GM-CSF, G-CSF) Stimulate Clonal Growth of Nonhematopoietic Tumor Cells. Blood, 73, 80-83.
[9]
Avalos, B.R., Gasson, J.C., Hedvat, C., et al. (1990) Human Granulocyte Colony-Stimulating Factor: Biologic Activities and Receptor Characterization on Hematopoietic Cells and Small Cell Lung Cancer Cell Lines. Blood, 75, 851-857.
[10]
Mueller, M.M. and Fusenig, N.E. (1999) Constitutive Expression of G-CSF and GM-CSF in Human Skin Carcinoma Cells with Functional Consequence for Tumor Progression. International Journal of Cancer, 83, 780-789.
https://doi.org/10.1002/(SICI)1097-0215(19991210)83:6<780::AID-IJC14>3.0.CO;2-C
[11]
Kikuchi, T., Nakahara, S. and Abe, T. (1996) Granulocyte Colony-Stimulating Factor (G-CSF) Production by Astrocytoma Cells and Its Effect on Tumor Growth. Journal of Neuro-Oncology, 27, 31-38. https://doi.org/10.1007/BF00146081
[12]
Brandstetter, T., Ninci, E., Bettendorf, H., et al. (2001) Granulocyte Colony-Stimulating Factor (G-CSF) Receptor Gene Expression of Ovarian Carcinoma Does Not Correlate with G-CSF Caused Cell Proliferation. Cancer, 91, 1372-1383.
https://doi.org/10.1002/1097-0142(20010401)91:7<1372::AID-CNCR1141>3.0.CO;2-E
[13]
Matsumoto, Y., Saiki, I., Murata, J., et al. (1991) Recombinant Human Granulocyte Colony-Stimulating Factor Inhibits the Metastasis of Hematogenous and Non-Hematogenous Tumors in Mice. International Journal of Cancer, 49, 444-449.
https://doi.org/10.1002/ijc.2910490323
[14]
Cosaert, J. and Quoix, E. (2002) Platinum Drugs in the Treatment of Non-Small-Cell Lung Cancer. British Journal of Cancer, 87, 825-833.
https://doi.org/10.1038/sj.bjc.6600540
[15]
Vansteenkiste, J., Vandebroek, J., Nackaerts, K., et al. (2003) Influence of Cisplatin-Use, Age, Performance Status and Duration of Chemotherapy on Symptom Control in Advanced Non-Small Cell Lung Cancer: Detailed Symptom Analysis of a Randomised Study Comparing Cisplatin-Vindesine to Gemcitabine. Lung Cancer, 40, 191-199.
[16]
Ramalingam, S. and Belani, C.P. (2004) State-of-the-Art Chemotherapy for Advanced Non-Small Cell Lung Cancer. Seminars in Oncology, 31, 68-74.
https://doi.org/10.1053/j.seminoncol.2003.12.017
[17]
Socinski, M.A. (2004) Cytotoxic Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Review of Standard Treatment Paradigms. Clinical Cancer Research, 10, 4210s-4214s. https://doi.org/10.1158/1078-0432.CCR-040009
[18]
Waterhouse, D.M., Reynolds, R.K. and Natale, R.B. (1993) Combined Carboplatin and Cisplatin. Limited Prospects for Dose Intensification. Cancer, 71, 4060-4066.
https://doi.org/10.1002/1097-0142(19930615)71:12<4060::AID-CNCR2820711242>3.0.CO;2-0
[19]
Kurihara, N., Kubota, T., Hoshiya, Y., et al. (1996) Pharmacokinetics of Cis-Diamminedichloroplatinum (II) Given as Low-Dose and High-Dose Infusions. Journal of Surgical Oncology, 62, 135-138.
https://doi.org/10.1002/(SICI)1096-9098(199606)62:2<135::AID-JSO10>3.0.CO;2-7
[20]
Miyanaga, N. and Akaza, H. (2001) Verify the Optimum Administration of Anticancer Agent—Cisplatin. Gan To Kagaku Ryoho, 28, 1339-1344.
[21]
Mosmann, T. (1983) Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. Journal of Immunological Methods, 65, 55-63.
[22]
Ohno, Y., Fukuda, K., Takemura, G., et al. (1999) Induction of Apoptosis by Gallic Acid in Lung Cancer Cells. Anticancer Drugs, 10, 845-851.
https://doi.org/10.1097/00001813-199910000-00008
[23]
Kawada, M., Ohno, Y., Li, Y., et al. (2001) Anti-Tumor Effect of Gallic Acid on LL-2 Lung Cancer Cells Transplanted in Mice. Anticancer Drugs, 12, 847-852.
https://doi.org/10.1097/00001813-200111000-00009
[24]
Li, Y.M., Ohno, Y., Minatoguchi, S., et al. (2003) Extracts from the Roots of Lindera Strychifolia Induces Apoptosis in Lung Cancer Cells and Prolongs Survival of Tumor-Bearing Mice. The American Journal of Chinese Medicine, 31, 857-869.
https://doi.org/10.1142/S0192415X03001545
[25]
Krause, D.S., Theise, N.D., Collector, M.I., et al. (2001) Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell. Cell, 105, 369-377.
[26]
Schmitt, R.M., Bruyns, E. and Snodgrass, H.R. (1991) Hematopoietic Development of Embryonic Stem Cells in Vitro: Cytokine and Receptor Gene Expression. Genes & Development, 5, 728-740. https://doi.org/10.1101/gad.5.5.728
[27]
Boneberg, E.M., Hareng, L., Gantner, F., et al. (2000) Human Monocytes Express Functional Receptors for Granulocyte Colony-Stimulating Factor That Mediate Suppression of Monokines and Interferon-Gamma. Blood, 95, 270-276.
[28]
Sloand, E.M., Kim, S., Maciejewski, J.P., et al. (2000) Pharmacologic Doses of Granulocyte Colony-Stimulating Factor Affect Cytokine Production by Lymphocytes in Vitro and in Vivo. Blood, 95, 2269-2274.
[29]
Siddik, Z.H. (2003) Cisplatin: Mode of Cytotoxic Action and Molecular Basis of Resistance. Oncogene, 22, 7265-7279. https://doi.org/10.1038/sj.onc.1206933
[30]
Boulikas, T. and Vougiouka, M. (2003) Cisplatin and Platinum Drugs at the Molecular Level. Oncology Reports, 10, 1663-1682.
[31]
Wang, G., Reed, E. and Li, Q.Q. (2004) Molecular Basis of Cellular Response to Cisplatin Chemotherapy in Non-Small Cell Lung Cancer. Oncology Reports, 12, 955-965.
[32]
Bussolino, F., Wang, J.M., Defilippi, P., et al. (1989) Granulocyte- and Granulocyte-Macrophage-Colony Stimulating Factors Induce Human Endothelial Cells to Migrate and Proliferate. Nature, 337, 471-473. https://doi.org/10.1038/337471a0
[33]
Natori, T., Sata, M., Washida, M., et al. (2002) G-CSF Stimulates Angiogenesis and Promotes Tumor Growth: Potential Contribution of Bone Marrow-Derived Endothelial Progenitor Cells. Biochemical and Biophysical Research Communications, 297, 1058-1061.
[34]
Arpinati, M., Green, C.L., Heimfeld, S., et al. (2000) Granulocyte-Colony Stimulating Factor Mobilizes T Helper 2-Inducing Dendritic Cells. Blood, 95, 2484-2490.
[35]
Klangsinsirikul, P. and Russell, N.H. (2002) Peripheral Blood Stem Cell Harvests from G-CSF-Stimulated Donors Contain a Skewed Th2 CD4 Phenotype and a Predominance of Type 2 Dendritic Cells. Experimental Hematology, 30, 495-501.