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L J Brandes

Publications and source records attributed to L J Brandes.

At least 19 recordsLinked to original sources
PubMed2005

Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases.

PURPOSE: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. MATERIALS AND METHODS: A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). RESULTS: Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. CONCLUSIONS: Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.

Adenocarcinoma↗
PubMed2002

Murine and human hematopoietic colony formation: a possible regulatory role for intracellular histamine.

Increasing number of data suggests that locally produced histamine is involved in regulation of hematopoiesis. In this study the granulocyte/macrophage (CFU-GM) colony formation by normal murine or human bone marrow cells, leukaemic colony formation (CFU-L) by a murine leukemia cell line (WEHI 3B), and colony formation by bone marrow cells from patients with chronic myeloid leukemia (CML) have been examined. We detected mRNA and protein expression of histidine decarboxylase (HDC), the only enzyme responsible for histamine synthesis both in normal bone marrow progenitor cells and in leukaemic progenitors. The significance of in situ generated histamine was shown on colony formation by inhibitory action of alphaFMH (blocking HDC activity, i.e. de novo histamine formation) and by N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl (DPPE) disturbing the interference of histamine with intracellular binding sites. These data provide further confirmation of the role of histamine in development and colony formation of bone marrow derived cells.

Animals↗
PubMed2000

Interaction of histamine and other bioamines with cytochromes P450: implications for cell growth modulation and chemopotentiation by drugs.

We have characterized microsomal and nuclear histamine sites, designated H(IC), through which this amine acts as an intracellular mediator of platelet aggregation and lymphocyte mitogenesis. A major proportion, at least, of the microsomal H(IC) sites are on cytochromes P450, an important family of microsomal enzymes that are present in all cells, but most abundant in the liver. These enzymes are involved in the metabolism of xenobiotics and natural substrates, including lipid hormones that modulate gene function and cell growth. We have shown that polyamines, hormones (including estrogen, testosterone and progesterone), antihormones (including tamoxifen and flutamide) and various antidepressants and antihistamines, all inhibit histamine binding to P450; we have postulated that, through binding to the heme moiety, intracellular histamine regulates cell function by modulating the catalytic activity of P450 enzymes, an action that may be perturbed by endogenous and exogenous substances. We now demonstrate that, in addition to histamine, melatonin and the biogenic amines dopamine, serotonin and noradrenaline bind to P450 isozymes and to cytochrome C. Thus, heme enzymes in general may represent common targets where multiple bioamines, hormones and drugs interact to influence cell function and growth.

Animals↗
PubMed2000

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.

PURPOSE: N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), an intracellular histamine (HA) antagonist with chemopotentiating and cytoprotective properties, is currently in phase 2 and 3 clinical trials in breast and prostate cancer. DPPE modulates growth at in vitro concentrations that antagonize HA binding to cytochromes P450 in rat liver microsomes. HA inhibits P450 metabolism of some drugs. Recent in vitro studies in human colon cancer cells have linked DPPE enhancement of paclitaxel, doxorubicin and vinblastine cytotoxicity to inhibition of the P-glycoprotein (P-gp) pump. Many substrates of P-gp are also substrates of CYP3A4, a P450 isozyme that metabolizes a variety of antineoplastic agents and is highly expressed in some malignant tissues. Therefore, we assessed whether (a) DPPE and HA interact at CYP3A4 and other P450 human isozymes, and (b) DPPE inhibits the catalytic activity of CYP3A4. METHODS: Using spectral analysis, we measured DPPE and HA binding to insect microsomes that express human P450 isozymes 1A1, 2B6, 2D6 or 3A4. Employing thin-layer chromatography, we assessed the metabolism of DPPE by each isozyme and DPPE inhibition of testosterone metabolism by CYP3A4 and by rat liver microsomes. RESULTS: (1) DPPE evoked "type I" (substrate site binding) absorbance-difference spectra with CYP2D6 (K(S) = 4.1 +/- 0.4 microM), CYP3A4 (K(S) = 31 +/- 15 microM) and CYP1A1 (K(S) = 40 +/- 9 microM), but not with CYP2B6. (2) In correspondence with the binding studies, DPPE was metabolized by CYP2D6, CYP3A4 and CYP1A1; no metabolism occurred with CYP2B6. (3) HA evoked "type II" (heme iron binding) absorbance-difference spectra with all four isozymes, with K(S) values in the range 80-600 microM. DPPE inhibited HA (600 microM) binding to CYP2D6 (IC50 = 4 microM, 95% CI= 1.8-8.9 microM) and CYP1A1 (IC50 = 135 microM: 95% CI = 100-177 microM), but stimulated HA (500 and 1000 microM) binding to CYP3A4 (EC50 = 155 microM, 95% CI = 104-231 microM). DPPE did not affect HA binding to CYP2B6. (4) DPPE inhibited the metabolism of testosterone by CYP3A4. The concentration/effect curve was biphasic: DPPE inhibited metabolism by 30% at the first site (IC50 = 3 microM, 95% CI = 0.5-25.5 microM), and an additional 70% inhibition occurred at the second site (IC50 = 350 microM, 95% CI = 215-570 microM). A similar result was observed with rat liver microsomes. CONCLUSION: DPPE is a substrate for CYP3A4, CYP2D6 and CYP1A1, but not CYP2B6. DPPE inhibits testosterone metabolism by interacting at two sites on CYP3A4, the first correlating with its K(S) value to bind the substrate site and the second, with its EC50 value to enhance HA binding to the heme iron. We postulate that (1) the inhibitory effect of DPPE on CYP3A4 activity is mediated directly at the substrate site and indirectly by its enhancement of the binding of HA to the heme moiety; (2) in tumor cells that express high constitutive levels of CYP3A4, potentiation of chemotherapy cytotoxicity by DPPE results, in part, from inhibition of CYP3A4-mediated metabolism and P-gp-mediated efflux of antineoplastic drugs; (3) in normal cells that express low constitutive levels of the isozyme, cytoprotection by DPPE results, in part, from induction of CYP3A4 and P-gp, resulting in an increase both in metabolism and efflux of antineoplastic drugs.

Adjuvants, Pharmaceutic↗
PubMed2000

Interactive binding at cytochrome P-450 of cell growth regulatory bioamines, steroid hormones, antihormones, and drugs.

The virtually universal family of P-450 isozymes contribute to the regulation of cell growth by modulating the levels of steroids and other lipid messengers for cytoplasmic and nuclear processes, including gene expression. In microsomes from rat liver cells, the concentration ( approximately 1 nmole/mg protein) of cytochromes P-450 approximates that of intracellular binding sites (K(d) 1.0-50 microM) for histamine. The potencies of certain therapeutic drugs to inhibit catalytic activity of, and histamine binding to, cytochromes P-450 in vitro were previously shown by us to be predictive of relative propensities to modulate tumor growth in rodents. Also, we demonstrated that growth-regulating polyamines potently interact with histamine at P-450. We now show that several classes of steroid hormones, antiestrogens, and antiandrogens, as well as various arylalkylamine drugs, all potently inhibit (3)H-histamine binding to cytochrome P-450 (K(i) values: testosterone 0.28 microM, progesterone 0.56 microM, flutamide 1.7 microM, tamoxifen 9.0 microM). Furthermore, all the various hormone and drug ligands are mutually inhibitory in their binding to cytochrome P-450; e.g., K(i) values of androstenedione and progesterone, to inhibit imipramine binding to P-450 (determined by spectral analysis), are 11 nM and 26 nM, respectively. The K(i) value of imiprimine to inhibit binding of androstenedione to P-450 is 3.5 microM. We estimate the total P-450 content in microsomes to be greater in male than in female rats and correlated with the number of binding sites for histamine, but not for steroids and drugs that appear to be more selective for P-450 isozymes. Thus, for at least some isozymes, the homeostatic role of the monooxygenases may be governed by histamine, modulated by endogenous ligands, and perturbed by many foreign molecules.

Animals↗
PubMed1998

Potent interaction of histamine and polyamines at microsomal cytochrome P450, nuclei, and chromatin from rat hepatocytes.

Histamine and polyamines have been implicated in the mediation of cell proliferation. Our previous work linked the growth-modulatory effects of histamine with its binding to intracellular sites in microsomes and nuclei of various tissues. In this study, we identify cytochrome P450 enzymes as a major component of microsomal intracellular sites in hepatocytes and demonstrate that polyamines compete with high affinity for histamine binding to them. Spectral measurement of histamine binding to P450 in liver microsomes resolved high and intermediate affinity binding sites (Ks1 = 2.4 +/- 1.6 microM; Ks2 = 90 +/- 17 microM) that corresponded to microsomal binding sites (Kd1 = 1.0 +/- 0.9 microM; Kd2 = 57 +/- 13 microM) resolved by 3H-histamine binding; additional low affinity (Kd3 approximately 3 mM), and probably physiologically irrelevant, sites were resolved only by 3H-histamine radioligand studies. As determined spectrally, treatment of microsomes with NADPH/carbon monoxide decreased histamine binding to P450 by about 90% and, as determined by 3H-histamine binding, abolished the high affinity sites and reduced by 85% the number of intermediate sites. Spermine competed potently for 3H-histamine binding: in microsomes, Ki = 9.8 +/- 5.8 microM; in nuclei, Ki = 13.7 +/- 3.1 microM; in chromatin, Ki = 46 +/- 33 nM. Polyamines inhibited the P450/histamine absorbance complex with the rank order of potency: spermine > spermidine >> putrescine. In contrast, histamine did not compete for 3H-spermidine binding in nuclei or microsomes, suggesting that polyamines modulate histamine binding allosterically. We propose that certain P450 isozymes that modulate gene function by controlling the level of oxygenated lipids, represent at least one common intracellular target of growth-regulatory endogenous bioamines and, as shown previously, of exogenous growth-modulatory drugs including antiestrogens, antiandrogens, and certain antidepressants and antihistamines.

Animals↗
PubMed1998

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

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 (i.v.) over 80 minutes. Doxorubicin (60 mg/m2) was administered i.v. 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 = or > 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.

Adult↗
PubMed1997

Salutary clinical response of prostate cancer to antiandrogen withdrawal: assessment of flutamide in an in vitro paradigm predictive of tumor growth enhancement.

Salutary clinical responses to withdrawal of flutamide have been widely reported, indicating the potential of this arylalkylamine antiandrogen to stimulate the growth of prostate cancer. Flutamide is known to inhibit cytochrome P450-mediated testosterone synthesis and metabolism. Our laboratory has shown that arylalkylamine potencies in three in vitro assays of P450 binding or function correspond to a propensity of the drugs to enhance tumor growth in vivo. Accordingly, we measured inhibition by flutamide of (a) histamine binding to cytochrome P450 in rat liver microsomes, as determined spectrally, (b) P450-mediated demethylation of aminopyrine, and (c) DNA synthesis in mouse spleen cells stimulated by concanavalin A, and we compared its potencies in these assays with those of other arylalkylamine pharmaceuticals. Flutamide inhibited histamine binding to P450 (Ki = 31 +/- 7 microM), aminopyrine demethylation (Ki = 39 +/- 2 microM), and mitogenesis (IC50 = 12 +/- 1 microM). In overall potency, it ranked with a group of eight drugs, including the antiestrogen tamoxifen, all linked with enhanced tumor growth. In the context of clinical observations that some patients with prostate cancer benefit from flutamide withdrawal, our findings underline concerns that many arylalkylamine drugs have the potential to stimulate the growth or development of malignancies, including prostate cancer. Tumor growth enhancement by flutamide and other arylalkylamines may result from drug perturbation and/or induction of histamine-binding P450 enzymes involved in the synthesis of steroid and eicosanoid mediators that regulate gene function and cell growth.

Aminopyrine N-Demethylase↗
PubMed1996

Enhancement of tumor growth by drugs with some common molecular actions.

A group of structurally related drugs representing diverse therapeutic classes share, among a number of pharmacological properties, enhancement of tumor growth in several rodent models of malignancy. One common action, the inhibition of histamine binding to and catalytic activity of cytochrome P450 monooxygenases, is highly correlated with potency to enhance tumor growth. Among members of this drug ensemble, the antiestrogen tamoxifen has been shown in controlled clinical studies to increase the incidence of uterine and gastrointestinal cancer and to accelerate the course of gastric cancer, and the tamoxifen analogue clomiphene has been linked to neuroblastoma and the tricyclic group of antidepressants to ovarian cancer. The determination of drug affinities for protein modulators of cell growth, proliferation, and transformation suggests a strategy for identifying at least some classes of chemicals that impart oncologic risks to humans.

Animals↗
PubMed1995

Can the clinical course of cancer be influenced by non-antineoplastic drugs?

Laboratory and anecdotal clinical evidence suggests that some common non-antineoplastic drugs may affect the course of cancer. The authors present two cases that appear to be consistent with such a possibility: that of a 63-year-old woman in whom a high-grade angiosarcoma of the forehead improved after discontinuation of lithium therapy and then progressed rapidly when treatment with carbamazepine was started, and that of a 74-year-old woman with metastatic adenocarcinoma of the colon that regressed when self-treatment with a nonprescription decongestant preparation containing antihistamine was discontinued. The authors suggest that epidemiologic studies are needed to investigate a possible association between non-antineoplastic drugs and the clinical course of cancer and that consideration should be given to discontinuing all nonessential medications for patients with cancer.

Adenocarcinoma, Mucinous↗
PubMed1995

N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic hormonally unresponsive prostate cancer.

PURPOSE: The intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine. HCl (DPPE), potentiates chemotherapy cytotoxicity to malignant cells but protects normal tissue, including bone marrow, gut, and hair. We assessed the response to and clinical toxicity of DPPE/cyclophosphamide therapy in 20 patients with advanced hormonally unresponsive prostate cancer, 19 of whom were symptomatic. PATIENTS AND METHODS: Subjects received a maximally tolerated dose of DPPE (6 mg/kg) intravenously (IV) over 80 minutes. Cyclophosphamide (600 to 800 mg/m2; maximum dose, 1,500 mg) was administered over the last 20 minutes of DPPE infusion. Treatments (usually outpatient) were given once weekly for 4 weeks, followed by a 1-week delay, and then 2 of every 3 weeks as long as the patient was deemed to benefit. RESULTS: Five of seven patients (71%) with measurable soft tissue disease had a partial remission (PR). Three of 16 (19%) with assessable bone disease responded (one complete remission [CR] and two PRs). Nine of 18 (50%) with an elevated serum level of prostate-specific antigen (PSA) had more than a 50% (mean +/- SD, 78% +/- 14%) decrease. Eleven of 13 (85%) with bone pain had partial or complete resolution of this symptom; the PSA level and bone scan improved in six and two of these subjects, respectively. Acute treatment toxicity consisted of nausea/vomiting (six of 20) and ataxia (20 of 20), which correlated with peak serum levels of DPPE. Delayed effects (24 to 48 hours) consisted mainly of tiredness and mild nausea; one patient developed hemorrhagic cystitis. Bone marrow and hair follicle toxicity was negligible in 14 and 15 patients, respectively. CONCLUSION: DPPE/cyclophosphamide appears to be an active regimen for metastatic prostate cancer, with the added benefit of relatively low toxicity.

Aged↗
PubMed1994

Enhanced cancer growth in mice administered daily human-equivalent doses of some H1-antihistamines: predictive in vitro correlates.

BACKGROUND: Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity. PURPOSE: We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. METHODS: Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups. RESULTS: The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor. CONCLUSION: Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo. IMPLICATION: These in vitro tests may prove valuable to screen potential tumor growth promoters.

Animals↗
PubMed1994

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 antineoplastic agents.

PURPOSE: We assessed N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE) potentiation of chemotherapy in vitro and performed a pharmacokinetic study and phase I/II trial of DPPE, combined with various single agents, in patients with advanced refractory cancer. PATIENTS AND METHODS: In vitro chemopotentiation by DPPE was assessed in drug-sensitive and -resistant (multidrug resistant-positive [MDR+]) human tumor cells using a colony survival assay. The effect of DPPE and verapamil on the intracellular concentration of daunorubicin in MDR+ cells was compared. For the clinical study, subjects with progressive malignancy received a weekly infusion of a maximally tolerated dose of DPPE (240 mg/m2) over 80 or 440 minutes, in conjunction with a single chemotherapy drug to which, in most cases, the patient's tumor was previously resistant. Concentrations of DPPE in blood and urine were determined by high-performance liquid chromatography (HPLC). RESULTS: In vitro, micromolar concentrations of DPPE potentiated (fivefold to 10-fold) chemotherapy cytotoxicity to both drug-sensitive and -resistant cells, but did not inhibit the p-glycoprotein pump; in vivo, serum levels of DPPE were 3 to 5 mumol/L at the end of 80 minutes and 1 to 2 mumol/L after 440 minutes of infusion. Of 48 patients monitored for a minimum of four DPPE/chemotherapy treatment cycles, 16 (33%) progressed, 12 (25%) stabilized, 12 (25%) improved, and eight (17%) responded (one complete and seven partial remissions). Four of 11 subjects who did not respond to the 80-minute infusion regimen improved with the 440-minute infusion; one had a partial remission of melanoma. In more than 600 patient-treatments, bone marrow toxicity was negligible (mean absolute neutrophil count [ANC] > 2.0 x 10(9)/L). Acute CNS symptoms associated with DPPE infusions were of relatively short duration (1 to 4 hours); delayed toxicity attributable to DPPE consisted of mild nausea and/or fatigue (1 to 2 days). CONCLUSION: Although preliminary, the results suggest that more structured trials should be performed to determine whether DPPE may increase the therapeutic index of certain chemotherapy drugs.

Adult↗
PubMed1992

Biochemical and ultrastructural studies suggest that the effects of thapsigargin on human platelets are mediated by changes in intracellular calcium but not by intracellular histamine.

The involvement of intracellular histamine in thapsigargin (Tg)-induced platelet aggregation was studied. Platelet aggregation induced by 0.25 and 0.5 microM Tg was not accompanied by a rise in intracellular histamine but a significant (p < 0.01) increase in the level of intracellular histamine was observed at 1 microM Tg. Preincubation of platelets with inhibitors of histamine metabolizing enzymes had little effect on intracellular histamine levels in platelets stimulated by 0.5 microM Tg. In addition, the inhibitors of histidine decarboxylase (HDC), alpha-methyl histidine (alpha-MH) and alpha-fluoromethyl histidine (alpha-FMH) failed to inhibit Tg-induced aggregation. The intracellular histamine receptor antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine. HCl (DPPE), inhibited Tg-induced aggregation but with IC50 values dependent on the concentration of agonist used. The inhibitory effects of DPPE on Tg-induced aggregation were not reversed by the addition of histamine to saponin-permeabilized platelets suggesting non-histamine mediated effects of DPPE on Tg-induced aggregation. Tg stimulated an increase in the cytosolic free calcium concentration which was unaffected by DPPE indicating that the effects of DPPE are also not due to the inhibition of mobilization of cytosolic calcium. The ultrastructural studies suggest that the major Tg-induced changes (pseudopod formation and granule centralization) are consistent with a primary role for Tg to mobilize calcium; DPPE had very little effect on these ultrastructural changes. The results indicate that the effects of Tg on human platelets are mediated by an increase in cytosolic calcium but not by intracellular histamine.

Blood Platelets↗
PubMed1992

Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses.

Tricyclic antidepressants, such as amitriptyline (Elavil), and the nontricyclic agent, fluoxetine (Prozac), bind to growth-regulatory intracellular histamine receptors, associated with anti-estrogen binding sites in microsomes and nuclei. The prototype anti-estrogen binding site/intracellular histamine receptor ligand, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, inhibits normal cell proliferation in vitro but stimulates tumor growth in vivo. Because of their structural similarity to N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, we carried out studies to determine whether amitriptyline and fluoxetine stimulate tumor growth and/or development in rodents at concentrations relevant to the treatment of human depression (equivalent human dose range, approximately 100-150 mg/day for amitriptyline and approximately 20-80 mg/day for fluoxetine). All experiments were performed blinded. In studies of growth stimulation of transplantable syngeneic tumors, groups of mice were inoculated s.c. with C-3 fibrosarcoma cells or given i.v. or s.c. injections of B16f10 melanoma cells, followed 24 h later by daily i.p. injections of saline, amitriptyline, or fluoxetine. Tumor latency (fibrosarcoma), aggregate tumor weight (s.c. injected melanoma), or time to death from pulmonary metastasis (i.v. injected melanoma) was determined; drug-induced stimulation of DNA synthesis in C-3 fibrosarcoma cells in vitro was correlated with tumor growth acceleration in vivo. In a mammary carcinogenesis model, the effects of chronic saline, amitriptyline, or fluoxetine administration on the rate and frequency of development of mammary tumors in rats fed dimethylbenzanthracene (DMBA) were compared. Eight of 20 amitriptyline- or fluoxetine-treated mice developed fibrosarcoma tumors by day 5, as compared to none of 20 saline controls (P less than 0.002). Similarly, 20 of 21 DMBA-treated rats receiving the antidepressant drugs developed 33 mammary tumors by week 15 as compared to 5 tumors in 4 of 7 DMBA-treated rats receiving saline (P less than 0.001). For both models, tumor latency decreased 30-40% and, in the DMBA model, tumor frequency increased greater than 2-fold in the antidepressant-treated rats as compared to controls. Stimulation of fibrosarcoma growth in vivo correlated with a corresponding bell-shaped drug-induced increase in DNA synthesis in vitro. While the median time to death from pulmonary metastases did not differ among groups given i.v. injections of melanoma cells, a significant (P less than 0.01) stimulation of growth of s.c. injected melanoma was observed in mice receiving the antidepressants.(ABSTRACT TRUNCATED AT 400 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Intracellular histamine and liver regeneration: high affinity binding of histamine to chromatin, low affinity binding to matrix, and depletion of a nuclear storage pool following partial hepatectomy.

We have demonstrated in rat hepatocytes that 3H-histamine binds specifically to novel low (microM) and high (nM) affinity sites, designated "HIC" to denote their intracellular location. Low affinity HIC sites are associated with microsomes, while both low and high affinity HIC sites are associated with the nucleus. A growth-regulatory action of intracellular histamine at HIC, independent of the rise in cytosolic calcium, has been demonstrated in mitogen-stimulated lymphocytes. We now report that the high affinity HIC sites in liver cell nuclei are associated exclusively with chromatin, while only low affinity sites are found in the residual material containing the nuclear matrix. Moreover, hepatocyte nuclei contain histamine (approximately 1 ng/mg protein), unaffected by incubation for up to 18 hours with the histidine decarboxylase inhibitor, alpha-FMH, suggesting a slow rate of turnover typical of a storage pool. A decrease in nuclear histamine parallels a rise in DNA synthesis in the first 24 hours after partial hepatectomy. Our findings support a role for a nuclear pool of pre-formed histamine in the mediation of liver regeneration.

Animals↗