Abstract
Paclitaxel is used as a single agent, and in combination with other drugs, as a standard of care in the treatment of squamous cell carcinoma of the head and neck (SCCHN). However, the use of paclitaxel for therapy of SCCHN may be accompanied by serious side effects. Paclitaxel is a known cytotoxic inhibitor of cell proliferation that acts by stabilizing microtubules and inducing apoptosis. Opioid growth factor (OGF), [Met5]-enkephalin, is an endogenous peptide that has tonically active inhibitory effects on the growth of SCCHN in vitro and in vivo. OGF action is rapid, reversible, mediated by the nuclear-associated OGF receptor (OGFr), and is not cytotoxic (nor apoptotic related). The present study was designed to examine whether a combination of chemotherapy with paclitaxel and biotherapy with OGF is more effective than either agent alone in inhibiting tumor growth. Moreover, focus was placed on whether there are changes in the side effects known to occur with paclitaxel alone, following this combined therapy. Human SCC-1 cells, derived from a well differentiated SCCHN, were transplanted into athymic mice. The mice were randomized to receive intraperitoneal (i.p.) injections of sterile saline (controls), OGF (10 mg/kg, daily), paclitaxel (8 mg/kg, every other day), or both paclitaxel (8 mg/kg, every other day) and OGF (10 mg/kg, daily) beginning on the day of tumor inoculation. OGF, but not paclitaxel, delayed measurable and visible tumor appearance of mice with SCCHN. Treatment with paclitaxel, but not with other agents, had a marked effect on the body weights. Survival only was reduced in the paclitaxel group, with an average life span of 34.3±3.1 days recorded, in comparison to the 50-day survival (date of termination) for all other groups. Beginning after week 4 of tumor inoculation and drug treatment, the tumor weight of the paclitaxel/OGF group was significantly reduced from the control, OGF, and paclitaxel-exposed mice. The OGFr number of the SCCHN tumors was 2.1-fold greater in the animals exposed to OGF or paclitaxel, and elevated 38% in the paclitaxel/OGF group; significant differences from the control group were found for the OGF and paclitaxel groups. These data suggest that combined chemotherapy (i.e., paclitaxel) and biotherapy (OGF) provides a valuable alternative to the standard of care for SCCHN patients.
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References
Arbuck SG, Cannetta R, Onetto N, Christian MC (1993) Current dosage and schedule issues in the development of paclitaxel (Taxol). Semin Oncol 20:31–39
Carew JF, Shah JP (1998) Advances in multimodality therapy for laryngeal cancer. CA Cancer J Clin 48:211–228
Carpinterio A, Peinert S, Ostertag W, Zander AR, Hossfeld DK, Kuhlcke K, Eckert HG, Baum C, Hegewisch-Becker S (2002) Generic protection of repopulating hematopoietic cells with an improved MDR1-retrovirus allows administration of intensified chemotherapy following stem cell transplantation in mice. Int J Cancer 98:785–792
Forastiere AA, Shank D, Neuberg D, Taylor SG, DeConti RC, Adams G (1998) Final report of a phase II evaluation of paclitaxel with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer 82:2270–2274
Hussain M, Gadgeel S, Kucuk O, Du W, Salwen W, Ensley J (1999) Paclitaxel, cisplatin, and 5-fluorouracil for patients with advanced or recurrent squamous cell carcinoma of the head and neck. Cancer 86:2364–2369
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) Cancer statistics. CA Cancer J Clin 54:8–29
Kieback DG, Dagmar-Christiane F, Engehausen DG, Sauerbrei W, Oehler MK, Tong X-W, Aguilar-Cordova E (2002) Intraperitoneal adenovirus-mediated suicide gene therapy in combination with human ovarian cancer. Cancer Gene Ther 9:478–481
Krause CJ, Carey TE, Ott RW, Hurbis C, McClatchey KD, Regezi JA (1981) Human squamous cell carcinoma. Arch Otolaryngol 107:703–710
Kurbacher CM, Mallmann PK (1998) Chemoprotection in anticancer therapy: the emerging role of amifostine. Anticancer Res 18:2203–2210
Leonard CE, Chan DC, Chou T-C, Kumar R, Bunn PA (1996) Paclitaxel enhances in vitro radiosensitivity of squamous carcinoma cell lines of the head and neck. Cancer Res 56:5198–5204
Levin RJ, Wu Y, McLaughlin PJ, Zagon IS (1997) Expression of the opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor in head and neck squamous cell carcinoma. Laryngoscope 107:335–339
Leyvraz S, Ohnuma T, Lassus M, Holland JF (1985) Phase I study in patients with advanced cancer, intermittent intravenous bolus, and 24-hour infusion. J Clin Oncol 3:1385–1392
McLaughlin PJ, Levin RJ, Zagon IS (1999) Regulation of human head and neck squamous cell carcinoma growth in tissue culture by opioid growth factor. Int J Oncol 14:991–998
McLaughlin PJ, Levin RJ, Zagon IS (2000) The opioid growth factor receptor (OGFr) in human head and neck squamous cell carcinoma. Int J Mol Med 5:191–196
McLaughlin PJ, Levin RJ, Zagon IS (2003) Opioid growth factor (OGF) inhibits the progression of human squamous cell carcinoma of the head and neck transplanted into nude mice. Cancer Lett 199:209–217
McLaughlin PJ, Stack BC, Levin RJ, Fedok F, Zagon IS (2003) Defects in the OGF receptor (OGFr) in human squamous cell carcinoma of the head and neck. Cancer 97:1701–1710
McLaughlin PJ, Jaglowski JR, Verderame MF, Stack BC, LeureduPree AE, Zagon IS (2005) Enhanced growth inhibition of squamous cell carcinoma of the head and neck by combination therapy of paclitaxel and opioid growth factor. Int J Oncol 26:809–816
McLaughlin PJ, Stack BC, Braine KM, Ruda JD, Zagon IS (2004) Opioid growth factor (OGF) inhibition of a human squamous cell carcinoma of the head and neck in nude mice: dependency on the route of administration. Int J Oncol 24:227–232
Parkin DM, Pisani P, Ferlay J (1999) Global cancer statistics. CA Cancer J Clin 49:33–64
Schantz S, Harrison LB, Forastiere AA (1997) Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer principles and practice of oncology, 5th edn. Lippincott-Raven, Philadelphia, pp 741–801
Schiff PB, Horwitz SB (1980) Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 77:1561–1565
Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 277:665–667
Shah JP, Lydiatt W (1995) Treatment of cancer of the head and neck. CA Cancer J Clin 45:352–368
Shim WSN, Teh M, Mack POP, Ge R (2001) Inhibition of angiopoietin-1 expression in tumor cells by an antisense RNA approach inhibited xenograft tumor growth in immunodeficient mice. Int J Cancer 94:6–15
Shin DM, Khuri FR, Glisson BS, Ginsberg L, Papadimitrakopoulou VM, Clayman G, Lee JJ, Ang KK, Lippman SM, Hong WK (2001) Phase II study of paclitaxel, ifosafamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma. Cancer 91:1316–1323
Smith JP, Conter RL, Bingaman SI, Harvey HA, Mauger DT, Ahmad M, Demers LM, Stanley WB, McLaughlin PJ, Zagon IS (2004) Treatment of advanced pancreatic cancer with opioid growth factor: phase I. Anticancer Drugs 15:203–209
Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo DL (1998) Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol 18:3509–3517
Villena-Heinsen C, Friedrich M, Ertan AK, Farnhammer C, Schmidt W (1998) Human ovarian cancer xenografts in nude mice: chemotherapy trials with paclitaxel, cisplatin, vinorelbine and titanocene dichloride. Anticancer Drugs 9:557–563
Vokes EE, Haraf DJ, Stenson K, Stupp R, Malone D, Levin J, Weichselbaum RR (1995) The role of paclitaxel in the treatment of head and neck cancer. Semin Oncol 22:8–12
Wilson RP, McLaughlin PJ, Lang CM, Zagon IS (2000) The opioid growth factor, [Met5]-enkephalin, inhibits DNA synthesis during recornification of mouse tail skin. Cell Prolif 33:63–73
Zagon IS, McLaughlin PJ (2003) Opioids and the apoptotic pathway in human cancer cells. Neuropeptides 37:79–88
Zagon IS, Wu Y, McLaughlin PJ (1994) Opioid growth factor (OGF) inhibits DNA synthesis in mouse tongue epithelium in a circadian-rhythm-dependent manner. Am J Physiol 267:R645–R652
Zagon IS, Wu Y, McLaughlin PJ (1999) Opioid growth factor and organ development in rat and human embryos. Brain Res 839:313–322
Zagon IS, Roesener CD, Verderame MF, Ohlsson-Wilhelm BM, Levin RJ, McLaughlin PJ (2000) Opioid growth factor regulates the cell cycle of human neoplasias. Int J Oncol 17:1053–1061
Zagon IS, Verderame MF, Allen SS, McLaughlin PJ (2000) Cloning, sequencing, chromosomal location, and function of a cDNA encoding the opioid growth factor receptor (OGFr) in humans. Brain Res 856:75–83
Acknowledgments
This research was supported in part by a grant from Philip Morris USA Inc. and the Pennsylvania Department of Health. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions presented in this paper. Portions of this research were included in a medical student research project for Jeffrey Manning, and a Master’s degree in anatomy for Jeffrey Jaglowski. We thank Dr. Chris Hollenbeak, Departments of Health Evaluation Sciences and Surgery, Pennsylvania State University College of Medicine, for statistical analysis of tumor volumes. The technical assistance from Jody Hankins and Amanda Dunkle was greatly appreciated.
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Jaglowski, J.R., Zagon, I.S., Stack, B.C. et al. Opioid growth factor enhances tumor growth inhibition and increases the survival of paclitaxel-treated mice with squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol 56, 97–104 (2005). https://doi.org/10.1007/s00280-004-0929-4
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DOI: https://doi.org/10.1007/s00280-004-0929-4