Skip to main content
SpringerLink
Log in

The intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl, may potentiate doxorubicin in the treatment of metastatic breast cancer: Results of a pilot study

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl (DPPE) is a diphenylmethane analog of tamoxifen that antagonizes the intracellular binding of histamine to growth-regulatory sites, a proportion of which represents P450 enzymes, in microsomes and nuclei. We previously reported increased response rates and decreased myelotoxicity in patients with prostate and other cancers who received an intensive dose/schedule of DPPE plus single-agent chemotherapy. We now report the results of a study of DPPE combined with a standard dose/schedule of doxorubicin in twenty-three patients with metastatic breast cancer, sixteen of whom had received prior non-anthracycline chemotherapy.

DPPE (6 mg/kg) was infused intravenously (IV) over 80 minutes. Doxorubicin (60 mg/m2) was administered IV over the last 20 minutes of the DPPE infusion. Treatment was repeated every 3 weeks (maximum, 7 cycles). Patients achieving complete response (CR) were followed off treatment until relapse.

All patients were evaluable for toxicities and efficacy. Sixteen patients (69%; 95% C.I. = 47–87%) responded (7 CR and 9 PR). Eleven responders, including 6 with CR, had prior chemotherapy. Five responders (2CR, 3PR) had a poor (ECOG 3/4) performance status pre-treatment. Median CR duration was 11 (range 5–18) months. Hematological toxicity was low; GI toxicity (nausea/vomiting/dyspepsia) appeared somewhat higher than historical experience, but responded well to anti-emetics, ranitidine, and/or dexamethasone in most patients; a mean absolute drop in left ventricular ejection fraction of 8% occurred in 17 patients who received ⩾ 300 mg/m2 doxorubicin.

The observed response rate in DPPE/doxorubicin-treated patients appeared to be higher than historically reported for doxorubicin alone in this setting, suggesting a chemopotentiating effect of DPPE. A multi-centre trial of this regimen in an additional 32 patients with early metastatic breast cancer has been conducted by the Clinical Trials Group, National Cancer Institute of Canada, and a phase 3 study is planned.

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. Henderson IC: In: Harris JR, Hellman S, Henderson IC, Kinne DW (eds): Breast Diseases, Philadelphia, PA, Lippincott, pp 428–479, 1987

    Google Scholar 

  2. Sledge GW: Doxorubicin/paclitaxel combination chemotherapy for metastatic breast cancer: the Eastern Cooperative Oncology Group experience. Semin Oncol 22:Suppl 2, 123–125, 1995

    PubMed  Google Scholar 

  3. Falkson G, Falkson CI, Falkson H: In: Powles TJ, Smith IE (eds) Medical Management of Breast Cancer, London, Martin Dunitz, pp 139–152, 1991

    Google Scholar 

  4. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial. J Clin Oncol 13: 2483–2489, 1995

    PubMed  Google Scholar 

  5. de Graaf H, Willemse PHB, de Vries EGE et al.: Intensive chemotherapy with autologous bone marrow transfusion as primary treatment in women with breast cancer and more than five involved axillary lymph nodes. Eur J Cancer 30A: 150–153, 1994

    Article  PubMed  Google Scholar 

  6. Gianni AM, Siena S, Bregni M et al.: Efficacy, toxicity, and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: Five-year results. J Clin Oncol 15: 2312–2321, 1997

    PubMed  Google Scholar 

  7. Brandes LJ, Hermonat MW: A diphenylmethane derivative specific for the antiestrogen binding site in rat liver microsomes. Biochem Biophys Res Commun 123: 724–728, 1984

    PubMed  Google Scholar 

  8. Brandes LJ, LaBella FS: Identification of intracellular histamine receptors (HIC) that regulate cell proliferation. Adv Biosci 89: 31–41, 1993

    Google Scholar 

  9. LaBella FS, Brandes LJ: Enhancement of tumour growth by drugs with some common molecular actions. Mol Carcinogenesis 16: 68–76, 1996

    Article  Google Scholar 

  10. Brandes LJ, LaBella FS, Warrington RC: Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists. J Natl Cancer Inst 83: 1329–1336, 1991

    PubMed  Google Scholar 

  11. Corbel S, Dy M: Evidence for histamine uptake by murine hematopoietic progenitors. Agents Actions 41: C113–114, 1994

    Article  PubMed  Google Scholar 

  12. Glavin GB, Brandes LJ: Antiulcerogenic and antisecretory effects of a novel diphenylmethane derivative and antiestrogen binding site ligand. Can J Physiol Pharmacol 66: 1139–1143, 1988.

    PubMed  Google Scholar 

  13. Brandes LJ, Simons KJ, Bracken SP, Warrington RC: Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl in combination with various single anticoplastic agents. J Clin Oncol 12: 1281–1290, 1994

    PubMed  Google Scholar 

  14. Brandes LJ, Bracen SP, Ramsey EW: N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic hormonally unresponsive prostate cancer. J Clin Oncol 13: 1398–1403, 1995

    PubMed  Google Scholar 

  15. Smith EJ, Vogelzang NJ, Goldberg HL et al.: High-dose cyclophosphamide (CTX) with granulocyte-macrophage colony stimulating factor (GM-CSF) in hormone-refractory prostatic cancer. Proc Am Soc Clin Oncol 11: 213 (Abstract), 1992

    Google Scholar 

  16. Brandes LJ, MacDonald KA, Bracken SP et al.: Results of human pilot study testing the hypothesis that the intracellular histamine antagonist DPPE increases the therapeutic index of doxorubicin. Adv Biosci 89: 375–401, 1993

    Google Scholar 

  17. Glavin GB, Gerrard JM: Characterization of the gastroprotective effects of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanaminc.HCl, a non-II1, non-II2 histamine antagonist. Digestion 47: 143–148, 1990

    PubMed  Google Scholar 

  18. Evans WK, Eisenhauer EA, Cormier Y, et al.: Phase II study of amonafide: Results of treatment and lessons learned from the study of an investigational agent in previously untreated patients with extensive small-cell lung cancer. J Clin Oncol 8: 390–395, 1990

    PubMed  Google Scholar 

  19. Pollen JJ, Shlaer WJ: Osteoblastic response to successful treatment of metastatic cancer of the prostate. Am J Roentgenol 132: 927–931, 1979

    Google Scholar 

  20. Henderson JC, Canellos GP: Cancer of the breast: the past decade. N Eng J Med 302: 78–80, 1980

    Google Scholar 

  21. Ahmann DL, Schaia DJ, Bisel HF, Hahn RG, Edmonson JH, Ingle JN: The effect on survival of initial chemotherapy in advanced breast cancer: polychemotherapy versus single drug. J Clin Oncol 5: 1928–1932, 1987

    PubMed  Google Scholar 

  22. Norris B, Pritchard K, James K, et al.: A phase III comparative study of vinorelbine (VNB) combined with doxorubicin (DOX) versus doxorubicin alone in recurrent/metastatic breast cancer (MBC): A National Cancer Institute of Canada (NCIC CTG) study. Proc Amer Soc Clin Oncol 15:98, 1996

    Google Scholar 

  23. Speyer JL, Green MD, Dubin N, et al.: Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast. Am J Med 78: 555–563, 1985

    Article  PubMed  Google Scholar 

  24. Shapira J, Gottfried M, Lishner M, Ravid M: Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen: A prospective randomized evaluation. Cancer 65: 870–873, 1990

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Hematology/Oncology, Department of Medicine, Faculty of Medicine, University of Manitoba, Canada

    Lorne J. Brandes

  2. Manitoba Cancer Treatment and Research Foundation, Winnipeg, Manitoba, Canada

    Lorne J. Brandes & Susan P. Bracken

Authors
  1. Lorne J. Brandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan P. Bracken
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brandes, L.J., Bracken, S.P. The intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine.HCl, may potentiate doxorubicin in the treatment of metastatic breast cancer: Results of a pilot study. Breast Cancer Res Treat 49, 61–68 (1998). https://doi.org/10.1023/A:1005909808529

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005909808529

Search

Navigation