N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE;tesmilifene),a chemopotentiating agent with hormetic effects on DNA synthesis in vitro,may improve survival in patients with metastatic breast cancer

Abstract

N,N -diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer (P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated.

Keywords

experimental tumors doxorubicin tesenilifene horemetic effects

References

Chabner BA , Roberts TG Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 2005; 5: 65-72.

Buzdar AU Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. Oncologist 2003; 8: 335-41.

Kaklamani VG , Gradishar WJ Epirubicin versus doxorubicin: which is the anthracycline of choice for the treatment of breast cancer? Clin Breast Cancer 2003; 4 (Suppl 1): S26-33.

Nowak AK , Wilcken NR , Stockler MR , Hamilton A. , Ghersi D. Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer. Lancet Oncol 2004; 5: 372-80.

Zhou BP , Li Y. , Hung MC HER-2/Neu signalling and therapeutic approaches in breast cancer. Breast Dis 2002; 15: 13-24.

Baselga J. Herceptin alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials. Oncology 2001; 61 (Suppl 2): 14-21.

Reyno L. , Seymour L. , Tu D. , et al. Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19. J Clin Oncol 2004; 22: 269-76.

Brandes LJ , Bracken SP 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 1998; 49: 61-8.

Khoo K. , Brandes LJ , Reyno L. et al. Phase II trial of N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine. HCl and doxorubicin chemotherapy in metastatic breast cancer: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 1999; 17: 3431-7.

10.

Chevallier B. , Mosseri V. , Dauce JP , Bastit P. , Julien JP , Asselain B. A prognostic score in histological node negative breast cancer. Br J Cancer 1990; 61: 436-40.

11.

Thomas H. , Coley HM Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 2003; 10: 159-65.

12.

Brandes LJ , Hermonat MW A diphenylmethane derivative specific for the antiestrogen binding site found in rat liver microsomes. Biochem Biophys Res Commun 1984; 123: 724-8.

13.

Sutherland RL , Murphy LC , Foo MS , Green MD , Whybourne AM , Krozowski ZS High affinity antiestrogen binding site distinct from the estrogen receptor. Nature 1980: 288: 273-5.

14.

Watts CK , Sutherland RL High affinity specific antiestrogen binding sites are concentrated in rough microsomal membranes of rat liver. Biochem Biophys Res Commun 1984; 120: 109-15.

15.

Brandes LJ , Hogg GR Study of the in vivo antiestrogenic action of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine. HCl (DPPE), a novel intracellular histamine antagonist and selective antiestrogen binding site ligand. J Reprod Fert 1990; 89: 59-67.

16.

Brandes LJ , Queen GM , LaBella FS N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (DPPE), a chemopotentiating and cytoprotective agent in clinical trials: Interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs . Cancer Chemother Pharmacol 2000; 45; 298-304.

17.

de Wildt SN , Kearns GL , Leeder JS , van den Anker JN Cytochrome P450 3A: ontogeny and drug disposition . Clin Pharmacokinet 1999; 37: 485-505.

18.

Katoh M. , Nakajima M. , Yamazaki H. , Yokoi T. Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport. Eur J Pharm Sci 2001; 12: 505-13.

19.

Ling V. Multidrug resistance: molecular mechanisms and clinical relevance. Cancer Chemother Pharmacol 1997; 40 (Suppl): S3-8.

20.

Menendez AT , Raventos-Suarez C. , Fairchild C. , et al. Mechanism of action of DPPE, a chemosensitizing agent. Proc Amer Assoc Cancer Res 1998; 39: 3462 (abstract).

21.

Kroeger EA , Brandes LJ Evidence that tamoxifen is a histamine antagonist. Biochem Biophys Res Commun 1985; 134: 750-5.

22.

Brandes LJ , Bogdanovic RP , Cawker MD , LaBella FS Histamine and growth: interaction of antiestrogen binding site ligands with a novel histamine site that may be associated with calcium channels. Cancer Res 1987; 47: 4025-31.

23.

LaBella FS , Brandes LJ Enhancement of tumor growth by drugs with some common molecular actions. Mol Carcinogen 1996; 16: 68-76.

24.

Kahlson G. , Rosengren E. Histamine formation as related to growth and protein synthesis. In: Biogenic Amines as Physiological Regulators ( Blum JJ , Ed.) Englewood-Cliffs NJ, Prentice-Hall 1970; 223-38.

25.

Nebert DW Proposed role of drug-metabolizing enzymes: Regulation of steady state levels of the ligands that affect growth, homeostasis, differentiation and neuroendocrine functions. Mol Endocrinol 1991; 5: 1204-14.

26.

Reiger MA , Ebner R. , Bell DR , Kiessling A. , et al. Identification of a novel mammary-restricted cytochrome P450, CYP4Z1, with overexpression in breast carcinoma. Cancer Res 2004; 64: 2357-64.

27.

Brandes LJ , Queem GM , LaBella FS Displacement of histamine from liver cells and cell components by ligands for cytochromes P450. J Cell Biochem 2002; 85: 820-4.

28.

Brandes LJ , LaBella FS , Warrington RC Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists. J Natl Cancer Inst 1991; 18: 1329-36.

29.

Brandes LJ , Beecroft WA , Hogg GR Stimulation of in vivo tumor growth and phorbol ester-induced inflammation by N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine. HCl, a potent ligand for intracellular histamine receptors. Biochem Biophys Res Commun 1991; 179: 1297-1304.

30.

Warrington RC A novel approach for improvong the efficacy of experimental cancer chemotherapy using combinations of anticancer drugs and L-histidinol. Anticancer Res 1986; 6: 451-64.

31.

Moya-Garcia AA , Medina MA , Sanchez-Jimenez F. Mammalian histidine decarboxylase: from structure to function. Bioessays 2005 ; 27: 57-63.

32.

Glavin GB , Gerrard JM Characterization of the gastro-protective effects of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine. HCl, a non-H1, non-H2 histamine antagonist. Digestion 1990; 47: 143-8.

33.

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 in combination with various single antineoplastic agents. J Clin Oncol 1998; 12: 1281-90.

34.

Warrington RC , Fang WD Reversal of the multidrug-resistant phenotype of Chinese hamster ovary cells by L-histidinol. J Natl Cancer Inst 1989; 81: 798-803.

35.

Rolland PH , Martin PM , Jacquemier J. , Rolland AM , Toga M. Prostaglandin in human breast cancer: Evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells. J Natl Cancer Inst 1980; 64: 1061-70.

36.

Honn KV , Tang DG , Gao IA , et al. 12-Lipoxygenases and 12(S)-HETE: role in cancer metastasis. Cancer Metastasis Rev 1994; 13: 365-96.

37.

Tong W. -G, Ding, X-Z. , Adrian TE The mechanisms of lioxygenase inhibitor-induced apoptosis in human breast cancer cells. Biochem Biophys Res Commun 2002 ; 296: 942-8.

38.

Brandes LJ , Bracken SP , Ramsey EW N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine. HCl in combination with cyclophosphamide: an active low toxicity for metastatic hormonally unresponsive prostate cancer. J Clin Oncol 1995; 13: 1398-403.