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

<jats:p> 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 &lt; 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. </jats:p>

Tamoxifen Prevents Apoptosis and Follicle Loss from Cyclophosphamide in Cultured Rat Ovaries1

“…Tamoxifen is a commonly used cancer drug that has been tested extensively in combination with other antineoplastic agents [3,4]. Additionally, tamoxifen and other SERMs are being developed as protectants against neurologic and brain injury [5,6] and potentiators of cancer treatments [7][8][9][10][11].…”

“…Tamoxifen prevents follicle loss following exposure to two widely used and ovotoxic cancer drugs, cyclophosphamide and doxorubicin, in preclinical in vivo models [16]. Additionally, recent work has shown similar prevention of radiationmediated ovarian toxicity using tamoxifen as a countermeasure [6,7]. It is unclear from previous work whether the protective effects of tamoxifen against cyclophosphamide toxicity in the ovary are direct ovarian actions or actions via such indirect mechanisms as alterations in gonadotropin release or hepatic drug metabolism [15].…”

Tesmilifene modifies brain endothelial functions and opens the blood–brain/blood–glioma barrier

“…; Georges et al . ), but the mechanism is not fully understood (Brandes ). Since tesmilifene blocked the activity of two other important BBB efflux pumps Bcrp and Mrp‐1, the sensitization of tumor cells by tesmilifene and its beneficial adjuvant action on efflux pumps cannot be excluded.…”

“…Tesmilifene acts via several receptors and signaling pathways (Brandes ). Some potentially important pathways regulating BBB permeability were selected among them.…”

Pathophysiological implications of neurovascular P450 in brain disorders

“…CYP3A4/5 metabolizes antineoplastic molecules (e.g., ifosfamide, vinblastine, etoposide, and doxorubicin) and contributes to drug resistance in patients with cancer [55]. The presence of P450s in tumor cells might be part of a pleiotropic response to tumor development, because certain P450 enzymes provide an essential cellular function by inactivating antitumor compounds, such as 2-methoxyestradiol, or by activating tumor-promoting compounds, such as 4-hydroxyestradiol [56].…”