Annals of Surgical Oncology

, Volume 10, Issue 4, pp 463–468 | Cite as

Thermal Enhancement of New Chemotherapeutic Agents at Moderate Hyperthermia

  • Faheez Mohamed
  • Pierre Marchettini
  • O. Anthony Stuart
  • M. Urano
  • Paul H. Sugarbaker
Original Articles


Background: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. We have studied the effect of moderate hyperthermia (41.5°C) on the cytotoxicity of five new chemotherapeutic agents (docetaxel, paclitaxel, irinotecan, oxaliplatin, and gemcitabine) and melphalan against a spontaneous murine fibrosarcoma.

Methods: The tumor was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath set at 41.5°C for 30 minutes when the tumor reached 34 mm3. Chemotherapy was administered intraperitoneally immediately before hyperthermia. Tumor response was studied by the mean tumor growth time and the mean tumor growth delay time.

Results: Hyperthermia significantly increased the tumor growth times of the animals treated with docetaxel, irinotecan, and gemcitabine at low dose and these drugs plus oxaliplatin at high dose. Docetaxel at high dose showed the greatest control of tumor growth by hyperthermia, with a 26% reduction. Concerning the taxanes, paclitaxel cytotoxicity was not enhanced by hyperthermia, but docetaxel was enhanced by hyperthermia at both doses of drug.

Conclusions:Moderate hyperthermia increases the cytotoxicity of docetaxel, irinotecan, and gemcitabine on mouse fibrosarcoma. Paclitaxel did not show heat enhancement. Oxaliplatin and docetaxel showed greater heat enhancement when the drug dose was high.

Key Words:

Hyperthermia Intraperitoneal chemotherapy Thermal enhancement Animal tumors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Engelhard R. Hyperthermia and drugs. Recent Results Cancer Res 1987;104:136–203.Google Scholar
  2. 2.
    Hahn GM. Potential for therapy of drugs and hyperthermia. Cancer Res 1979;39:2264–8.PubMedGoogle Scholar
  3. 3.
    Dahl O, Mella O. Enhanced effect of combined hyperthermia and chemotherapy (bleomycin, BCNU) in a neurogenic rat tumor BT4A in vivo. Anticancer Res 1982;2:359–64.PubMedGoogle Scholar
  4. 4.
    Schiff PB, Fant J, Horowitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature 1979;22:665–7.CrossRefGoogle Scholar
  5. 5.
    Thigpen JT. Chemotherapy for advanced ovarian cancer. Overview of randomised trials. Semin Oncol 2000;27:11–6.PubMedGoogle Scholar
  6. 6.
    Cortes JE, Padzur R. Docetaxel. J Clin Oncol 1995;13:2643–55.PubMedGoogle Scholar
  7. 7.
    Verweij J, Clavel M, Chevalier B. Paclitaxel (Taxol™) and docetaxel (Taxotere™). Not simply two of a kind. Ann Oncol 1994;5:495–505.PubMedGoogle Scholar
  8. 8.
    Barton JS, Vandivort DL, Heacock DH, Coffman JA, Trygg KA. Microtubule assembly kinetics. Changes with solution conditions. Biochem J 1987;247:505–11.PubMedGoogle Scholar
  9. 9.
    Leal BZ, Meltz ML, Mohan N, Kuhn J, Prihoda TJ, Herman TS. Interaction of hyperthermia with Taxol in human MCF-7 breast adenocarcinoma cells. Int J Hyperthermia 1999;15:225–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Rougier P, Bugat R. CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Semin Oncol 1996;23(1 Suppl 3):34–41.Google Scholar
  11. 11.
    Kondo T, Ueda K, Kano E. Combined effects of hyperthermia and CPT-11 on DNA strand breaks in mouse mammary carcinoma FM3A cells. Anticancer Res 1995;15:83–6.PubMedGoogle Scholar
  12. 12.
    Rietbroek RC, van de Vaart PJ, Haveman J, et al. Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells. J Cancer Res Clin Oncol 1997;123:6–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Elias D, Bonnay M, Puizillou JM, et al. Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Ann Oncol 2002;13:267–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Grindey GB, Broder GB, Hertel LW, et al. Antitumor activity of 2′, 2′-difluorodeoxycytidine (LY 188011). Proc Am Assoc Cancer Res 1986;27:296.Google Scholar
  15. 15.
    Hertel LW, Boder GB, Kroin JS, et al. Evaluation of the antitumor activity of gemcitabine (2′2′-difluoro-2′ deoxycytidine). Cancer Res 1990;50:4417–22.PubMedGoogle Scholar
  16. 16.
    Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU refractory pancreas cancer. Ann Oncol 1996;7:347–53.PubMedGoogle Scholar
  17. 17.
    Hui YF, Reitz J. Gemcitabine. A cytidine analogue active against solid tumors. Am J Health Syst Pharm 1997;54:162–70.PubMedGoogle Scholar
  18. 18.
    Plunkett W, Huang P, Xu Y, Heinemann V, Grunewald R, Gandhi V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 1995;22(4 Suppl 11):3–10.Google Scholar
  19. 19.
    Van Bree C, Beumer C, Rodermond HM, Haveman J, Bakker PJM. Effectiveness of 2′,2′difluorodeoxycytidine (gemcitabine) combined with hyperthermia in rat R-1 rhabdomyosarcoma in vitro and in vivo. Int J Hyperthermia 1999;15:549–56.PubMedCrossRefGoogle Scholar
  20. 20.
    Urano M, Majima H, Miller R, Kahn J. Cytotoxic effect of 1,3 bis (2-chloroethyl)-N-nitrosourea at elevated temperatures: Arrhenius plot analysis and tumor response. Int J Hyperthermia 1991;7:499–510.PubMedCrossRefGoogle Scholar
  21. 21.
    Urano M, Gerweck LE, Epstein R, Cunningham M, Suit HD. Response of spontaneous murine tumor to hyperthermia: factors which modify the thermal response in vivo. Radiat Res 1980;83:312–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Pestieau SR, Stuart OA, Chang D, Jacquet P, Sugarbaker PH. Pharmacokinetics of intraperitoneal gemcitabine in a rat model. Tumori 1998;84:708–13.Google Scholar
  23. 23.
    Urano M, Kuroda M, Nishimura Y. For the clinical application of thermochemotherapy given at mild temperatures. Int J Hyperthermia 1999;15:79–107.PubMedCrossRefGoogle Scholar
  24. 24.
    Dahl O. Mechanisms of thermal enhancement of chemotherapeutic cytotoxicity. In: Urano M, Douple E, eds. Hyperthermia and Oncology. Utrecht, The Netherlands: VSP, 1994:29.Google Scholar
  25. 25.
    Dumontet C, Bodin F, Michal Y. Potential interactions between antitubulin agents and temperature: implications for modulation of multidrug resistance. Clin Cancer Res 1998;4:1563–6.PubMedGoogle Scholar
  26. 26.
    Rietbroek RC, Katschinski DM, Reijers MH, et al. Lack of thermal enhancement for taxanes in vitro. Int J Hyperthermia 1997;13:525–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Othman Goto S, Lee JB, Taimura A, Matsumoto T, Kosaka M. Hyperthermic enhancement of the apoptotic and antiproliferative activities of paclitaxel. Pharmacology 2001;62:208–12.CrossRefGoogle Scholar
  28. 28.
    Cividalli A, Livdi E, Ceciarelli F, et al. Hyperthermia and paclitaxel–epirubicin chemotherapy: enhanced cytotoxic effect in a murine mammary adenocarcinoma. Int J Hyperthermia 2000;16:61–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Sharma D, Chelvi TP, Kaur J, Ralhan R. Thermosensitive liposomal taxol formulation: heat-mediated targeted drug delivery in murine melanoma. Melanoma Res 1998;8:240–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Knox JD, Mitchel RE, Brown DL. Effects of taxol and taxol/hyperthermia treatments on the functional polarization of cytotoxic T lymphocytes. Cell Motil Cytoskeleton 1993;24:129–38.PubMedCrossRefGoogle Scholar
  31. 31.
    Katschinski DM, Robins HI. Hyperthermic modulation of SN-38 induced topoisomerase I DNA cross-linking and SN-38 cytotoxicity through altered topoisomerase I activity. Int J Cancer 1999;80:104–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Haveman J, Rietbroek RC, Geerdink A, Van Rijn J, Bakker PJ. Effect of hyperthermia on the cytotoxicity of 2′,2′-difluorodeoxycytidine (gemcitabine) in cultured SW 1573 cells. Int J Cancer 1995;62:627–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Sarosy G, Leyland-Jones B, Soochan P, Cheson BD. The systemic administration of intravenous melphalan. J Clin Oncol 1988;6:1768–82.PubMedGoogle Scholar
  34. 34.
    Urano M, Ling CC. Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro. Int J Hyperthermia 2002;18:307–15.PubMedCrossRefGoogle Scholar
  35. 35.
    Lienard D, Eggermont AM, Kroon BBR, Koops HS, Lejeune FJ. Isolated limb perfusion in primary and recurrent melanoma: indications and results. Semin Surg Oncol 1998;14:202–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Koops HS, Eggermont AM, Lienard D, et al. Hyperthermic isolated limb perfusion for the treatment of soft tissue sarcomas. Semin Surg Oncol 1998;14:210–4.CrossRefGoogle Scholar
  37. 37.
    Knox JD, Mitchel REJ, Brown DL. Effects of hyperthermia on microtubule organization and cytolytic activity of murine cytotoxic T lymphocytes. Expl Cell Res 1991;194:275–83.CrossRefGoogle Scholar
  38. 38.
    Clark BD, Brown IR. Altered expression of a heat shock protein in the mammalian nervous system in the presence of agents which affect microtubule stability. Neurochem Res 1987;12:819–23.PubMedCrossRefGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 2003

Authors and Affiliations

  • Faheez Mohamed
    • 1
  • Pierre Marchettini
    • 1
  • O. Anthony Stuart
    • 1
  • M. Urano
    • 2
  • Paul H. Sugarbaker
    • 1
    • 3
  1. 1.Washington Cancer InstituteWashington
  2. 2.Memorial Sloan-Kettering Cancer CenterNew York
  3. 3.The Washington Cancer InstituteWashington Hospital CenterWashington

Personalised recommendations