Skip to main content

Advertisement

SpringerLink
Log in

Combination chemotherapy with gemcitabine and biotherapy with opioid growth factor (OGF) enhances the growth inhibition of pancreatic adenocarcinoma

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Gemcitabine is the standard of care for advanced pancreatic neoplasia, and exerts its effect through inhibition of DNA synthesis. However, gemcitabine has limited survival benefits. Opioid growth factor (OGF) is an autocrine-produced peptide that interacts with the nuclear receptor, OGFr, to inhibit cell proliferation but is not cytotoxic or apoptotic. The present study was designed to examine whether a combination of chemotherapy with gemcitabine and biotherapy with OGF is more effective than either agent alone in inhibiting pancreatic cancer growth in vitro and in vivo. The combination of OGF (10−6 M) and gemcitabine (10−8 M) reduced MIA PaCa-2 cell number from control levels by 46% within 48 h, and resulted in a growth inhibition greater than that of the individual compounds. OGF in combination with 5-fluorouracil also depressed cell growth more than either agent alone. The action of OGF, but not gemcitabine, was mediated by a naloxone-sensitive receptor, and was completely reversible. OGF, but no other endogenous or exogenous opioids, altered pancreatic cancer growth in tissue culture. The combination of OGF and gemcitabine also repressed the growth of another pancreatic cancer cell line, PANC-1. MIA PaCa-2 cells transplanted into athymic mice received 10 mg/kg OGF daily, 120 mg/kg gemcitabine every 3 days; 10 mg/kg OGF daily and 120 mg/kg gemcitabine every 3rd day, or 0.1 ml of sterile saline daily. Tumor incidence, and latency times to tumor appearance, of mice receiving combined therapy with OGF and gemcitabine, were significantly decreased from those of the control, OGF, and gemcitabine groups. Tumor volumes in the OGF, gemcitabine, and OGF/gemcitabine groups were markedly decreased from controls beginning on days 14, 12, and 8, respectively, after tumor cell inoculation. Tumor weight and tumor volume were reduced from control levels by 36–85% in the OGF and/or gemcitabine groups on day 45 (date of termination), and the group of mice exposed to a combination of OGF and gemcitabine had decreases in tumor size of 70% and 63% from the OGF or the gemcitabine alone groups, respectively. This preclinical evidence shows that combined chemotherapy (e.g. gemcitabine) and biotherapy (OGF) provides an enhanced therapeutic benefit for pancreatic cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jemal A, Murray T, Ward E, Samuels A., Twari RC, Ghafoor A., Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30

    PubMed  Google Scholar 

  2. Parkin DM, Pisani P, Ferlay J (1999) Global cancer statistics. CA Cancer J Clin 49:33–64

    CAS  PubMed  Google Scholar 

  3. Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Eng J Med 326:455–465

    CAS  Google Scholar 

  4. Akerele CE, Rybalova I, Kaufman HL, Mani S (2003) Current approaches to novel therapeutics in pancreatic cancer. Invest New Drugs 21:113–129

    Article  CAS  PubMed  Google Scholar 

  5. Li D, Xie K, Wolff R, Abbruzzese (2004) Pancreatic cancer. Lancet 363:1049–1057

    Article  CAS  PubMed  Google Scholar 

  6. Diaz-Rubio E (2004) New chemotherapeutic advances in pancreatic, colorectal, and gastric cancers. Oncologist 9:282–294

    Article  CAS  PubMed  Google Scholar 

  7. Pasetto LM, Jirillo A, Stefani M, Monfardini S (2004) Old and new drugs in systemic therapy of pancreatic cancer. Crit Rev Oncol Hematol 49:135–151

    PubMed  Google Scholar 

  8. Zagon IS, Smith JP (2004) Treatment options in pancreatic cancer. Hospital Pharmacy Europe Nov/Dec:1–2

  9. Huang P, Chubb S, Hertel L, Grindley GB, Plunkett W (1991) Action of 2′, 2′-difluorodeoxycitine on DNA synthesis. Cancer Res 51:6110–6117

    Google Scholar 

  10. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GB (1990) Evaluation of the antitumor activity of gemcitabine (2′2′-difluoro-2′-deoxycytidine). Cancer Res 50:4417–4422

    Google Scholar 

  11. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassof P, Nelson R, Dorr FA, Stephens CD, von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer. A randomized trial. J Clin Oncol 15:2403–2413

    CAS  PubMed  Google Scholar 

  12. Philip PA (2002) Gemcitabine and platinum combinations in pancreatic cancer. Cancer 95:908–911

    Google Scholar 

  13. Ryan DP, Kulke MH, Fuchs CS, Grossbard ML, Grossman SR, Morgan JA, Earle CC, Shivdasani R, Kim H, Mayer RJ, Clark JW (2002) A phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 94:97–103

    Google Scholar 

  14. Zagon IS, McLaughlin PJ (2004) Opioid growth factor (OGF) inhibits anchorage-independent growth in human cancer cells. Int J Oncol 24:1443–1448

    CAS  PubMed  Google Scholar 

  15. Zagon IS, Hytrek SD, Smith JP, McLaughlin PJ (1997) Opioid growth factor (OGF) inhibits human pancreatic cancer transplanted into nude mice. Cancer Lett 112:167–175

    Article  CAS  PubMed  Google Scholar 

  16. Zagon IS, Smith JP, McLaughlin PJ (1999) Human pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factor. Int J Oncol 14:577–584

    CAS  PubMed  Google Scholar 

  17. 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

    CAS  PubMed  Google Scholar 

  18. Zagon IS, Smith JP, Conter R, McLaughlin PJ (2000) Identification and characterization of opioid growth factor receptor in human pancreatic adenocarcinoma. Int J Mol Med 5:77–84

    CAS  PubMed  Google Scholar 

  19. Zagon IS, McLaughlin PJ (2003) Opioids and the apoptotic pathway in human cancer cells. Neuropeptides 37:79–88

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Google Scholar 

  22. Yunis AA, Arimura GK, Russin DJ (1977) Human pancreatic carcinoma (MIA PaCa-2) in continuous culture: sensitivity to asparaginase. Int J Cancer 19:128–135

    CAS  Google Scholar 

  23. Lieber M, Mazzetta J, Nelson-Rees W, Kaplan M, Todaro G (1975) Establishment of a continuous tumor-cell line (PANC-1) from a human carcinoma of the exocrine pancreas. Int J Cancer 15:741–747

    Google Scholar 

  24. Sato N, Ohta T, Kitagawa H, Kayahara M, Ninomiya I, Fushida S, Fujimura T, Nishimura G, Shimizu K, Miwa K (2004) FR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cells. Int J Oncol 24:679–685

    CAS  PubMed  Google Scholar 

  25. Schwarz RE, McCarty TM, Peralta EA, Diamond DJ, Ellenhorn JD (1999) An orthotopic in vivo model of human pancreatic cancer. Surgery 126:562–567

    Article  CAS  PubMed  Google Scholar 

  26. Shim WSN, Teh M, Mack POP, Ge R (2001) Inhibition of angiopoietin-1 expression in tumor cells by antisense RNA approach inhibited xenograft tumor growth in immunodeficient mice. Int J Cancer 94:6–15

    Google Scholar 

  27. Fueger BJ, Hamilton G, Raderer M, Pangerl T, Traub T, Angelberger P, Baumgartner G, Dudczak R, Virgolini I (2001) Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells. J Nucl Med 42:1856–1862

    CAS  PubMed  Google Scholar 

  28. Shi X, Liu S, Kleeff J, Friess H, Buchler MW (2002) Acquired resistance of pancreatic cancer cells towards 5-fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology 62:354–362

    Article  CAS  PubMed  Google Scholar 

  29. Faivre S, Raymond E, Woynarowski JM, Cvitkovic E (1999) Supraadditive effect of 2′,2′′-difluorodeoxycitidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol 44:117–123

    Google Scholar 

  30. Yip-Schneider MT, Sweeney CJ, Jun S-H, Crowell PL, Marshall MS (2001) Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther 298:976–985

    Google Scholar 

  31. Shore S, Raraty GT, Ghaneh P, Neoptolemos JP (2003) Review article: chemotherapy for pancreatic cancer. Aliment Pharmacol Ther 18:1049–1069

    Google Scholar 

  32. Di Paolo A, Danesi R, Del Tacca M (2004) Pharmacogenetics of neoplastic diseases: new trends. Pharmacol Res 49:331–342

    Google Scholar 

  33. Buchsbaum DJ, Bonner JA, Grizzle WE, Stackhouse MA, Carpenter M, Hicklin DJ, Bohlen P, Raisch KP (2002) Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation. Int J Radiat Oncol Biol Phys 54:1180–1193

    Article  CAS  PubMed  Google Scholar 

  34. Schultz RM, Merriman RL, Toth JE, Zimmermann JE, Hertel LW, Andis SL, Dudley DE, Rutherford PG, Tanzer LR, Grindey GB (1993) Evaluation of new anticancer agents against the MIA PaCa-2 and PANC-2 human pancreatic carcinoma xenografts. Oncol Res 5:223–228

    CAS  PubMed  Google Scholar 

  35. Bold RJ, Virudachalam S, McConkey DJ (2001) Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 100:11–17

    Article  CAS  PubMed  Google Scholar 

  36. Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H, Ungefroren H (2004) Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int J Cancer 109:182–188

    Google Scholar 

  37. Blagosklonny MV (2000) Cell death beyond apoptosis. Leukemia 14:1502–1508

    Article  CAS  PubMed  Google Scholar 

  38. Jacobs AD (2002) Gemcitabine-based therapy in pancreas cancer. Cancer Suppl 85:923–927

    Google Scholar 

  39. Corrie P, Mayer A, Shaw J, D‘Ath S, Blagden S, Blesing C, Price P, Warner N (2002) Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients. Br J Cancer 87:716–719

    Google Scholar 

  40. Gasparini G (2001) Metronomic scheduling: The future of chemotherapy. Lancet Oncol 2:733–740

    Article  CAS  PubMed  Google Scholar 

  41. Kerbel RS, Klement G, Pritchard KI, Kamen B (2002) Continuous low-dose anti-angiogenic/metronomic chemotherapy: from the research laboratory into the oncology clinic. Ann Oncol 13:73–80

    Article  Google Scholar 

  42. Jaglowski JR, Zagon IS, Stack BC, Verderame MF, Leure-duPree AE, Manning JD, McLaughlin PJ (2005) Opioid growth factor (OGF) enhances tumor growth inhibition and increases the survival of paclitaxel-treated mice with squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol, (in press)

  43. McLaughlin PJ, Jaglowski JR, Verderame MF, Stack BC, Leure-duPree 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 (in press)

  44. 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

    CAS  PubMed  Google Scholar 

  45. 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

    Article  CAS  PubMed  Google Scholar 

  46. McLaughlin PJ, Zagon IS, Skitzki J (1999). Human neuroblastoma cell growth in tissue culture is regulated by opioid growth factor. Int J Oncol 14:373–380

    CAS  PubMed  Google Scholar 

  47. Bisignani, GJ, McLaughlin PJ, Ordille SD, Beltz MS, Jarowenko MV, Zagon IS (1999) Human renal cell cancer proliferation in tissue culture is tonically inhibited by opioid growth factor. J Urol 162:218–191

    Google Scholar 

  48. Zagon IS, Hytrek SD, Lang CM, Smith JP, McGarrity TJ, Wu Y, McLaughlin PJ (1996) Opioid growth factor ([Met5]-enkephalin) prevents the incidence and retards the growth of human colon cancer. Am J Physiol 271:R780–R786

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Portions of this research were included as partial fulfillment for the Master’s Degree in Anatomy (Jeffery Jaglowski).This research was supported in part by Philip Morris USA Inc. and Philip Morris International, and The Pennsylvania Department of Health. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

Author information

Authors and Affiliations

  1. Department of Neural and Behavioral Sciences, H109, Milton S. Hershey Medical Center, The Pennsylvania State University, 500 University Drive, Room C3729, Hershey, PA, 17033, USA

    Ian S. Zagon, Jeffrey R. Jaglowski, Alphonse E. Leure-duPree & Patricia J. McLaughlin

  2. Department of Medicine, H109, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA, 17033, USA

    Michael F. Verderame & Jill P. Smith

Authors
  1. Ian S. Zagon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey R. Jaglowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael F. Verderame
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jill P. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alphonse E. Leure-duPree
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patricia J. McLaughlin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian S. Zagon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zagon, I.S., Jaglowski, J.R., Verderame, M.F. et al. Combination chemotherapy with gemcitabine and biotherapy with opioid growth factor (OGF) enhances the growth inhibition of pancreatic adenocarcinoma. Cancer Chemother Pharmacol 56, 510–520 (2005). https://doi.org/10.1007/s00280-005-1028-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-1028-x

Keywords

Search

Navigation