Skip to main content

Advertisement

SpringerLink
Log in

Activity of gemcitabine in a human tumor cloning assay as a basis for clinical trials with gemcitabine

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

2′,2′-difluorodeoxycytidine (LY 188011, Gemcitabine, Gemzar®) has recently been approved both in Europe for the treatment of patients with non-small cell lung cancer and in the United States for patients with pancreatic cancer. Since the initial discovery of the compound, we have been evaluating the in vitro activity of gemcitabine against human tumor colony-forming units taken directly from patients and growing in soft agar (in the human tumor cloning assay — HTCA).

A total of 315 specimens have had gemcitabine tested against them with 44% giving evaluable results. Gemcitabine has been found to be active against colony-forming units from patients with non-small cell lung, breast, ovarian, and pancreatic cancers. A concentration-dependent in vitro response was noted with a higher in vitro response rate noted at 20 μg/ml than at 2.0 μg/ml. Based on subsequent clinical phase II data, the HTCA correctly predicted the wide spectrum of the clinical activity of gemcitabine.

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

Similar content being viewed by others

References

  1. Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197:461–463, 1977

    PubMed  CAS  Google Scholar 

  2. Salmon SE, Hamburger AW, Soehnlen B: Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. NEJM 298:1321–1327, 1978

    PubMed  CAS  Google Scholar 

  3. Von Hoff DD, Clark GM, Stogdill BJ, Sarosdy MF, O'Brien MT, Casper JT, Mattox DE, Page CP, Cruz AB, Sandbach JF: Prospective clinical trial of a human tumor cloning system. Cancer Res 43:1926–1931, 1983

    Google Scholar 

  4. Von Hoff DD, Sandbach JF, Clark GM, Turner JN, Forseth BF, Piccart MJ, Colombo N, Muggia FM: Selection of cancer chemotherapy for a patient by an in vitro assay versus a clinician. J Natl Cancer Inst 82:110–116, 1990

    Google Scholar 

  5. Heinemann V, Hertel L, Grindey GB, Plunkett W: Comparison of the pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-b-D-arabinofuranosylcytosine. Cancer Res 48:4024–4031, 1988

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  7. Hanauske A-R, Degen D, Marshall MH, Hilsenbeck SG, Grindey GB, Von Hoff DD: Activity of 2′,2′-difluorodeoxycytidine (Gemcitabine) against human tumor colony-forming units. Anticancer Drugs 3:143–146, 1992

    Article  PubMed  CAS  Google Scholar 

  8. Hanauske A-R, Hanauske U, Von Hoff DD: The human tumor cloning assay in cancer research and therapy: A review with clinical correlations. Curr Probl Cancer 9:1–50, 1985

    PubMed  CAS  Google Scholar 

  9. Perez E, Eckardt J, Hilsenbeck S, Rothenberg M, Degen D, Von Hoff DD: Activity of cytotoxic agents against non-small cell lung cancer specimens using a human tumor cloning assay. Proc Am Assoc Cancer Res 35:203, 1994

    Google Scholar 

  10. Hanauske A-R, Von Hoff DD: Clinical correlations with the human tumor cloning assay. Cancer Invest 3:541–551, 1985

    PubMed  CAS  Google Scholar 

  11. O'Rourke TJ, Brown TD, Havlin K, Kuhn JG, Craig JB, Burris HA, Satterlee PG, Tarassoff F, Von Hoff DD: Phase I clinical trial of gemcitabine given as an intravenous bolus on 5 consecutive days. Eur J Cancer 30A(3):417–418, 1994

    Article  PubMed  Google Scholar 

  12. Brown T, O'Rourke T, BuRRIs H, Kuhn J, Tarasoff P, Cagnola J, Rodriguez G, Von Hoff D: A phase I trial of gemcitabine (LY188011) administered intravenously every two weeks. Proc Am Soc Clin Oncol 10:115, 1991

    Google Scholar 

  13. Pollera CF, Ceribelli A, Crecco M, Calabresi F: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 5(2):182–184, 1994

    PubMed  CAS  Google Scholar 

  14. Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL: Difluorodeoxycytidine (GEMCITABINE): a phase II study in patients with advanced breast cancer. Proc Am Soc Clin Oncol 12:A57, 1993

    Google Scholar 

  15. Moore DF, Jr, Pazdur R, Daugherty K, Tarassoff P, Abbruzzese JL: Phase II study of gemcitabine in advanced colorectal adenocarcinoma. Invest New Drugs 10(4):323–325, 1992

    Article  PubMed  Google Scholar 

  16. Fink U, Molle B, Daschner H, Ermisch S, Loffel J, Herrmann R: Phase II study of gemcitabine in metastatic colorectal cancer. Proc Am Soc Clin Oncol 11:A507, 1992

    Google Scholar 

  17. Abbmzzese J, Pazdur R, Ajani J, Daugherty K, Tarassoff P, Levin B: A phase II trial of gemcitabine (DFDC) in patients (pts) with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 10:A456, 1991

    Google Scholar 

  18. Sessa C, Aamdal S, Wolff I, Eppelbaum R, Smyth JF, Sulkes A, Ten Bokkel Huinink W, Vermorken J, Wanders J, Franklin H: Gemcitabine in patients with advanced malignant melanoma or gastric cancer: phase II studies of the EORTC Early Clinical Trials Group. Ann Oncol 5(5):471–472, 1994

    PubMed  CAS  Google Scholar 

  19. Christman K, Kelsen D, Saltz L, Tarassoff PG: Phase II trial of gemcitabine in patients with advanced gastric cancer. Cancer 73(1):5–7, 1994

    Article  PubMed  CAS  Google Scholar 

  20. Catimel G, Vermorken JB, Clavel M, de Mulder P, Judson I, Sessa C, Piccart M, Bruntsch U, Verweij J, Wanders J: A phase II study of gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 5(6):543–547, 1994

    PubMed  CAS  Google Scholar 

  21. Clavel M, Vermorken JB, Judson I, Wagener T, Hatty S, Wanders J: Gemcitabine in an active drug in patients with squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 11:A808, 1992

    Google Scholar 

  22. Anderson H, Lund B, Bach F, Thatcher N, Walling J, Hansen HH: Single-agent activity of weekly gemcitabine in advanced non-small cell lung cancer: a phase II study. J Clin Oncol 12(9):1821–1826, 1994

    PubMed  CAS  Google Scholar 

  23. Abratt RP, Bezwoda WR, Falkson G, Goedhals L, Hacking D, Rugg TA: Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol 12(8):1535–1540, 1994

    PubMed  CAS  Google Scholar 

  24. Cormier Y, Eisenhauer E, Muldal G, Gregg R, Ayoub J, Goss G, Stewart D, Tarasoff P, Wong D: Gemcitabine is an active new agent in previously untreated extensive small cell lung cancer (SCLC). A study of the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 5(3):283–285, 1994

    PubMed  CAS  Google Scholar 

  25. Anderson H, Thatcher N, Walling J, Lund B: Gemcitabine and palliation of symptoms in non-small cell lung cancer (NSCLS). Proc Am Soc Clin Oncol 13:A1238, 1994

    Google Scholar 

  26. Abratt R, Bezwoda W, Fankson G, Goedhals L, Hacking D, Rugg T: Efficacy and safety of gemcitabine in non-small cell lung cancer (NSCLC): phase II study results. Proc Am Soc Clin Oncol 12:A1130, 1993

    Google Scholar 

  27. Cormier Y, Eisenhauer E, Gregg R, Ayoub J, Goss G, Stewart D, Muldal A, Tarassoff P: Gemcitabine: an active new agent in patients (pts) with previously untreated small cell lung cancer (SCLC). A phase II trials of the NCI Canada Clinical Trials Group (NCIC CTG). Proc Am Soc Clin Oncol 12:A1097, 1993

    Google Scholar 

  28. Shephard FA, Gatzemeier U, Gotfried M, Weynants P, Cottier B, Groen H, Rosso R, Mattson K, Cortes-Funes H, Tonato M: An extended phase II study of gemcitabine in non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 12:A1096, 1993

    Google Scholar 

  29. Thatcher N, Anderson H, Lund B, Hansen H: Gemcitabine in the treatment of non-small cell lung cancer. Ann Oncol 3(Suppl 5):198, 1992

    Google Scholar 

  30. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP: Phase II study of gemcitabine (2′,2′-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86(20):1530–1533, 1994

    PubMed  CAS  Google Scholar 

  31. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP: Phase II study of gemcitabine in previously platinum-treated ovarian cancer (OC) patients (pts). An update. Proc Am Soc Clin Oncol 12:A834, 1993

    Google Scholar 

  32. Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, Trochanowski B, Tarassoff PG: Phase II trial of gemcitabine (2′,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12(1):29–34, 1994

    Article  PubMed  CAS  Google Scholar 

  33. Carmichael J, Fink U, Russell RC, Spittle MF, Harris A, Spiessel G, Blatter J: Phase II study of gemcitabine in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 12:A698, 1993

    Google Scholar 

  34. Mertens WC, Eisenhauer EA, Moore M, Venner P, Stewart D, Muldal A, Wong D: Gemcitabine in advanced renal cell carcinoma. A phase II study of National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 4(4):331–332, 1993

    PubMed  CAS  Google Scholar 

  35. Weissbach L, de Mulder P, Osieka R, Ermisch S, Jakse G: Phase II study of gemcitabine in renal cancer. Proc Ara Soc Clin Oncol 11:A689, 1992

    Google Scholar 

  36. Grunewald R, Kantarjian H, Keating MJ, Abbruzzese J, Tarassoff P, Plunkett W: Pharmacologically directed design of the dose rate and schedule of 2′,2′-difluorodeoxycytidine (gemcitabine) administration in leukemia. Cancer Res 50:6823–6829, 1990

    PubMed  CAS  Google Scholar 

  37. Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN, Plunkett W: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9(3):491–498, 1991

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio, 78229, San Antonio, TX, USA

    Daniel D. Von Hoff

Authors
  1. Daniel D. Von Hoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the San Antonio Drug Development Team

Rights and permissions

Reprints and permissions

About this article

Cite this article

Von Hoff, D.D., the San Antonio Drug Development Team. Activity of gemcitabine in a human tumor cloning assay as a basis for clinical trials with gemcitabine. Invest New Drugs 14, 265–270 (1996). https://doi.org/10.1007/BF00194529

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00194529

Key words

Search

Navigation