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PubMed2002

Retinoic acid modulates the ability of macrophages to participate in the induction of the angiogenic phenotype in head and neck squamous cell carcinoma.

Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of angiogenesis and are of prognostic value in some neoplasms. Specimens from head and neck squamous cell carcinomas (HNSCC) often contain large numbers of TAMs. In addition, experimental evidence has demonstrated that HNSCC tumor cells can attract and activate macrophages to participate in the expression of the angiogenic phenotype. These findings suggest that antiangiogenic therapies for HNSCC must include strategies that will block the recruitment of macrophages into the tumor microenvironment. We investigated the ability of retinoic acid (RA) to modulate the ability of tumor cells to recruit and activate monocytes for participation in tumor angiogenesis. Owing to a decrease in the secretion of MCP-1 and transforming growth factor-beta 1 (TGF-beta 1), tumor cells treated with RA were unable to induce peripheral blood monocyte (PBM) chemotaxis. Also, as a result of the decrease in TGF-beta 1 secretion, RA-treated tumor cells were unable to activate macrophages for secretion of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In addition to its affects on tumor cells, RA also directly altered the ability of monocytes to participate in the tumor angiogenesis process. PBM exposed to RA were unable to migrate toward inducers of PBM such as MCP-1 and TGF-beta 1. Finally, RA decreased the ability of tumor-activated macrophages to secrete IL-8 and VEGF. These data demonstrate alternative mechanisms by which RA may modulate angiogenesis in the tumor microenvironment. In addition, it underscores the necessity to develop antiangiogenic treatment protocols that can block each of the ways in which new blood vessel growth is induced in tumor microenvironments.

Carcinoma, Squamous Cell↗

PubMed2001

Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages.

Animals↗

PubMed1990

Hormone and cytotoxic drug responsiveness of cultured human breast cancer cells resistant to specific hormones.

Attempts have been made to develop sublines of MCF-7 cells resistant to the growth-inhibitory actions of medroxyprogesterone acetate (MPA), dexamethasone (DEX), anti-oestrogens or high-dose oestradiol (E2) by prolonged exposure to high hormone concentrations. While high degrees of resistance to MPA, DEX and E2 were achieved, cells remained anti-oestrogen-sensitive after prolonged treatment with 4 microM tamoxifen (TAM) or the anti-oestrogen LY 117018 (LY). Cells resistant to DEX were also resistant to MPA, while cells resistant to high-dose E2 remained sensitive to TAM. Cells resistant to MPA and E2 appeared to be less responsive to cytotoxic drugs than wild-type cells, while resistance to DEX was associated with increased sensitivity. The responses of tumours to cytotoxic drugs may be affected by prior endocrine therapy.

Breast Neoplasms↗

PubMed1992

Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy.

Eight patients with epithelial ovarian carcinoma persisting after chemotherapy, selected for having a residual tumor no larger than 1 cm in diameter, were treated intra-peritoneally (i.p.) with recombinant interferon-gamma twice weekly for 3 months. Toxicity consisted of fever and malaise in all patients and a transient rise in hepatic enzyme levels in 3 patients. The cytotoxic function of peripheral blood and peritoneal tumor-associated lymphocytes (TAL) and macrophages (TAM), was studied using cell lines as targets. I.p. IFN-gamma augmented the cytotoxic activity of lymphocytes and mononuclear phagocytes: stimulation was more marked and more frequently observed with TAL and occasionally TAM than with blood effectors, suggesting preferential modulation at the site of tumor growth and IFN administration. Surgical laparotomy revealed that 1 patient had a complete response, 2 a partial response and 2 had stable disease, while 3 patients had progressive disease. In this small series of patients there was no obvious, strict correlation between immunomodulation by IFN-gamma and clinical response. These results indicate that, in contrast to its lack of activity in advanced ovarian carcinoma, IFN-gamma has definite immunomodulatory and antitumor activity in the presence of limited tumor burden.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

The pure antiestrogen ICI 182,780 binds to a high-affinity site distinct from the estrogen receptor.

Both estrogen receptor-positive (ER+), tamoxifen-sensitive (5-21) and tamoxifen-resistant (5-23) subclones of the parental MCF-7 breast cancer cell line were used in competitive ligand binding studies involving either [3H]ICI 182,780 or 4-OH-[3H]tamoxifen (4OHT) displacement by unlabelled estradiol (E2) or the antiestrogens (AE) 4OHT and ICI 182,780. Neither radioligand was displaced significantly by E2 over a range of concentrations; binding was predominantly inhibited by the corresponding radio-inert ligand. Scatchard analysis of the data revealed that the binding capacities of both cell lines for ICI 182,780 were approximately 7-fold greater than the previously determined number of ER sites per cell, with the affinity being an order of magnitude less than that of E2 for ER. No difference was found between the TAM-sensitive and -resistant cells in their binding of either AE. When cells were preincubated with either E2, TAM or 4OHT at a high, fixed concentration to block the ER or AE binding sites (AEBS), respectively, displaceable binding of [3H]ICI 182,780 was still observed, indicating binding at a site other than the classical ER or previously described AEBS. Our results suggest that there is a specific, saturable and relatively high-affinity binding site for ICI 182,780 in MCF 5-21 and MCF 5-23 breast cancer cells. However, the physiological relevance of this binding site requires further clarification because in cell growth assays, E2 (at 1/10 the dose of ICI 182,780) overcame the inhibitory effect of the antiestrogen in both of the cell lines.

Binding Sites↗

PubMed1985

Molecular analysis of instability in flower pigmentation of Antirrhinum majus, following isolation of the pallida locus by transposon tagging.

The pal locus of Antirrhinum majus was cloned using the transposable element, Tam 3, as a probe. The pal clone was used to examine, at the molecular level, those aspects of instability previously observed phenotypically and genetically. The effects of temperature and of genetic background on excision of the element at pal are considered, and related quantitatively to the phenotype. We describe the identification of the transcript of the pal locus and show that insertion of Tam 3 blocks the production of a normal pal transcript in developing flower buds.

Journal Article↗

PubMed1995

Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes.

We have examined the mechanism of signal transduction by the hemidesmosomal integrin alpha 6 beta 4, a laminin receptor involved in morphogenesis and tumor progression. Immunoprecipitation and immune complex kinase assays indicated that antibody- or laminin-induced ligation of alpha 6 beta 4 causes tyrosine phosphorylation of the beta 4 subunit in intact cells and that this event is mediated by a protein kinase(s) physically associated with the integrin. Co-immunoprecipitation and GST fusion protein binding experiments showed that the adaptor protein Shc forms a complex with the tyrosine-phosphorylated beta 4 subunit. Shc is then phosphorylated on tyrosine residues and recruits the adaptor Grb2, thereby potentially linking alpha 6 beta 4 to the ras pathway. The beta 4 subunit was found to be phosphorylated at multiple tyrosine residues in vivo, including a tyrosine-based activation motif (TAM) resembling those found in T and B cell receptors. Phenylalanine substitutions at the beta 4 TAM disrupted association of alpha 6 beta 4 with hemidesmosomes, but did not interfere with tyrosine phosphorylation of Shc and recruitment of Grb2. These results indicate that signal transduction by the alpha 6 beta 4 integrin is mediated by an associated tyrosine kinase and that phosphorylation of distinct sites in the beta 4 tail mediates assembly of the hemidesmosomal cytoskeleton and recruitment of Shc/Grb2.

Adaptor Proteins, Signal Transducing↗

PubMed1993

Mechanism of action of estrogen on cancellous bone balance in tibiae of ovariectomized growing rats: inhibition of indices of formation and resorption.

Ovariectomy results in cancellous osteopenia in rat long bones, a condition that is prevented by treatment with estrogens. The purpose of these studies was to clarify the effects of estrogen on cancellous bone turnover using dynamic bone histomorphometry. Treatment of ovariectomized rats with diethylstilbestrol (DES) reduced the mineral apposition rate, double-label perimeter, osteoblast number, and osteoclast number, suggesting that the hormone had inhibitory effects on bone formation as well as bone resorption. However, we could not estimate the bone formation rate because of rapid resorption of tetracycline-labeled bone in the ovariectomized rat. The magnitude of loss was documented by a time course study: 58% of the tetracycline initially incorporated into the secondary spongiosa of the tibial metaphysis was resorbed after 11 days and 89% was resorbed after 22 days. Similarly, cancellous bone area was decreased by 67% after 11 days and by 88% after 22 days. Administration of either DES or tamoxifen (TAM) dramatically reduced resorption of tetracycline as well as the decrease in cancellous bone area. These results demonstrate that (1) estrogen prevents osteopenia in ovariectomized (OVX) rats, in part by inhibiting bone turnover, (2) TAM is an estrogen agonist on bone resorption, and (3) resorption of tetracycline-labeled bone leads to serious underestimation of the bone formation rate in OVX rats.

Animals↗

PubMed1984

Regulation of T- and B lymphocyte responses to mitogens by tumor-associated macrophages: the dependency on the stage of tumor growth.

This preliminary investigation was concerned with the hypothesis that macrophages associated with tumors induced to regress temporarily by the action of cyclophosphamide (CY) have the capacity to suppress local T- or B lymphocyte responses which otherwise might cause permanent regression. Cultures of adherent cells, predominantly tumor-associated macrophages ( TAMs ), isolated from two C57BL/6J (B6) sarcomas, MCA/76-9 and 76-64, after various periods of tumor growth or after CY injection (240 mg/kg) were shown to suppress or enhance the response of 10(6) B6 normal spleen cells to stimulation by concanavalin-A (Con A) or lipopolysaccharide (LPS). At any given time point, the extent of suppression or enhancement induced by adherent cells isolated from tumors after CY injection was similar to that induced by cells from progressing tumors and appeared to be more dependent on the time after the initial injection of tumor cells than on drug treatment per se. Thus, adherent cells suppressed Con A and LPS responses when they were isolated either from small (0.5 g) or large (greater than 1.5 g) progressing tumors or from tumors 4-9 days after CY injection. However, during the logarithmic phase of tumor growth or within 4 days of injecting CY, adherent cells enhanced spleen cell mitogenic responses, particularly to LPS stimulation. The cultures of putative TAMs isolated at the various time points were seen to contain varying proportions of polymorphonuclear cells (PMNs), the proportions coinciding with the period of reduced spleen cell mitogenic responses. Cultures prepared from small or large progressing tumors contained about 10% or 20-30% PMNs, respectively, while those from tumors tested during the log phase contained less than 5% PMNs. Cultures from tumors removed within 4 days of injecting CY contained less than 5% PMNs while those prepared from tumors tested at later times contained as high as 25% PMNs by 9 days after CY injection. A comparison of peritoneal PMNs and macrophages from non-tumor-bearing mice in terms of their ability to influence mitogenesis indicated that PMNs at high ratios (1 PMN:2 spleen cells) could suppress responses directly. Lower ratios had either small suppressive effects or no effects but in no case was enhancement of responses seen. Peritoneal macrophages suppressed responses at a ratio of 1 macrophage:10 spleen cells but enhanced responses at ratios of 1 macrophage:100 or 1,000 spleen cells. The overall data indicated that the microenvironment of the tumor site may modulate the functional activity of macrophages, or their subpopulations, during their potential regulation of T- and B-cell responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

The contribution of HIV fitness to the evolution pattern of reverse transcriptase inhibitor resistance.

All currently recommended anti-retroviral therapy protocols employ reverse transcriptase inhibitors (RTIs). However, mutations within the reverse transcriptase (RT) domain can lead to resistance to these agents and treatment failure. The contribution of the fitness of drug-resistant species to the evolution of RTI resistance has not been elucidated despite its potential implications for therapeutic strategies. In this study we utilized a competitive fitness assay to assess the relative fitness of 13 drug-resistant HIV-1 mutants in the presence and absence of inhibitor. Among these mutants were thymidine analog mutations (TAMs) such as 41L/210W/215Y and 67N/70R/219Q, as well as single mutants such as 103N and 181C that confer high-level resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine. These studies revealed that 67N/70R and 67N/70R/219Q were fitter than the 70R progenitor species, and the acquisition of 41L by 215Y substantially increased its fitness in the absence of drug. We also observed that 215Y was more fit than 70R and 67N/70R, and that 41L/215Y and 41L/210W/215Y were the most-fit species in the presence of zidovudine. Moreover, 103N was fitter than 181C without nevirapine but less fit with nevirapine. From these studies we conclude that viral fitness contributes substantially to the evolutionary pattern of TAMs suggesting that, as for protease inhibitor resistance, mutations can act in primary (increasing resistance) and secondary (increasing fitness) capacities. We also surmise that drug resistance and fitness are competing forces underlying the emergence of nevirapine resistant mutants 103N and 181C.

Anti-HIV Agents↗

PubMed2007

Efficacy and safety of tenofovir double-dose in treatment-experienced HIV-infected patients: the TENOPLUS study.

Drug resistance is an increasing problem in the treatment of HIV infection. Tenofovir has been shown to inhibit HIV replication even with thymidine-associated resistance mutations (TAMs) if they are limited to two or less. Double-dose of tenofovir disoproxil fumarate (TDF) (600 mg QD) was used to determine weather the drug could be virologically effective in patients harbouring HIV-strains resistant to nucleoside analogues (NRTI). A pilot, open, non-comparative add-on study, where patients failing a current antiretroviral regimen, with at least two TAMs, and naive for tenofovir, were given tenofovir 600 mg once-daily for 4 weeks, in addition to their current failing antiretroviral regimen. The primary end-point was the percentage of patients with plasma viral load (VL) reduction of at least 0.8 log(10) between baseline and week 4 (W4). Ten patients were enrolled. At baseline, the median viral load was 3.66 log(10) copies/ml (range 3.13-4.03) and the median CD4 cell count was 407/mm(3) (range 136-1102). The percentage of patients with reduction the viral load > or =0.8 log(10) was 40% at W4. After 4 weeks of treatment with tenofovir 600 mg, the median decrease in the viral load was -0.61 log(10) (range -0.05; -0.88) and the median gain of CD4 was +109/mm(3). Despite a twofold increase tenofovir plasma concentrations, no serious drug-related adverse event were recorded except for one patient experiencing an de Fanconi syndrome at week 2. This add-on pilot study supports the concept of double dose tenofovir to virologically overcome the decreased sensitivity of NRTI-resistant viruses. However, the safety of this regimen needs to be considered carefully.

Adenine↗

PubMed2004

Tracheal gas insufflation-augmented continuous positive airway pressure in a spontaneously breathing model of neonatal respiratory distress.

Respiratory distress syndrome (RDS) in neonates is characterized by labored breathing and poor gas exchange, often requiring ventilatory support. Continuous positive airway pressure (CPAP) is a preferred intervention to support spontaneous ventilatory efforts by sustaining lung volume recruitment, while it prevents derecruitment during exhalation by maintaining end-expiratory pressure. However, CO2 retention during CPAP often results in the need for mechanical ventilation. Since tracheal gas insufflation (TGI) promotes CO2 elimination by reducing prosthetic dead space, we hypothesized that TGI used with CPAP may reduce the need for more invasive therapies. The objective of this study was to evaluate the physiologic effect of TGI with CPAP in a spontaneously breathing model of acute lung injury with respect to gas exchange and pulmonary mechanics. Nineteen spontaneously breathing neonatal pigs (2.4 +/- 0.4 kg) were anesthetized, sedated, instrumented, and placed on CPAP at 5 cmH2O. All piglets were injured with intravenous oleic acid (0.08 ml/kg), and then randomized to receive CPAP with TGI (TGI; n = 9) or CPAP alone (control; n = 10). FiO2 was titrated at 0.05 every 15 min during the protocol to maintain SaO2 > 93%. Vital signs, arterial blood gases, pulmonary mechanics, and thoracoabdominal motion (TAM) were evaluated 30 min after injury and at 1-hr intervals for 4 hr. Following the 4-hr measurement, the piglets were sacrificed and the lungs were grossly examined. After initiation of treatment, we found that the PaCO2 was lower (33.1 +/- 5.0 vs. 47.0 +/- 10.3 mmHg; P < 0.01), while the oxygenation indices were greater (PaO2, SaO2, a/A ratio; P < 0.01) in the TGI group than with control animals. Subsequently, the pH was greater (7.45 +/- 0.08 vs. 7.36 +/- 0.08; P < 0.01) and closer to baseline values with TGI. By 4 hr, the FiO2 was titrated lower (0.37 +/- 0.06 vs. 0.49 +/- 0.15; P < 0.05) and ventilation was accomplished with a lower minute ventilation (MV) in the TGI group than in the control group (445 +/- 113 vs. 581 +/- 223 ml/kg/min; P < 0.01). Respiratory compliance was greater with TGI than control (0.76 +/- 0.13 vs. 0.63 +/- 0.11 ml/cmH2O/kg; P < 0.01), whereas resistance and TAM were similar between groups. We conclude that the use of TGI with CPAP in the treatment of RDS results in improved gas exchange and pulmonary mechanics. As such, TGI-augmented CPAP may prevent infants from requiring more invasive ventilation by reducing CO2 retention.

Animals↗

PubMed2002

A study of the facilitation of respiration in myotonic dystrophy.

BACKGROUND AND PURPOSE: Dystrophia myotonica or myotonic dystrophy is a progressive neuromuscular disorder in which patients demonstrate an irregular respiratory pattern and are particularly subject to cardiopulmonary compromise. The aim of the present study was to investigate the effects of both proprioceptive neuromuscular facilitation (PNF) and staged basal expansion (SBE) breathing exercises in subjects with myotonic dystrophy in two different positions: high support sitting and left side-lying. METHOD: A randomized, double-blind study design was used. Seven non-congenital myotonic dystrophy subjects took part in the study. Six 'treatment' levels were applied to each subject: resting in high support sitting; resting in left side-lying; PNF of deep breathing in high support sitting; PNF of deep breathing in left side-lying; SBE in high support sitting and SBE in left side-lying. The outcome measures employed were arterial oxygen saturation (SpO2) and heart rate, as measured by oximetry and thoraco-abdominal motion (TAM), and respiratory rate, as measured by a pneumograph. RESULTS: The PNF technique was found to be the main contributor to improvement in SpO2 for subjects with myotonic dystrophy, where a 2.2% increase was found in the high support sitting position and a 2.6% increase was found in the left side-lying position. There was an increase of between 377% and 556% in TAM during application of both treatment techniques, in either the high support sitting or left side-lying positions. Respiratory rate declined between 15% and 30% immediately after treatment application and heart rate dropped slightly by between 0.2% and 4.1%. CONCLUSION: The present study provides objective evidence that application of these respiratory physiotherapy interventions elicits an improvement in respiratory function in subjects with myotonic dystrophy. Further research into the physiological effects of these techniques could explore the mechanisms responsible for improvement in respiratory indices.

Adult↗

PubMedDate not supplied

Altered uterine sensitivity to oxytocin and prostaglandin F2 alpha in dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinoma: the effects of tamoxifen and/or recombinant human interferon alpha 2b therapy.

This study aimed to investigate the long-term toxicity of a preventive regimen of tamoxifen (TAM) and recombinant human interferon alpha 2b (rHuIFN alpha 2b) on the uterine responsiveness of tumour-bearing rats. The experimental tumour was induced by dimethylbenz(a)anthracene (DMBA) in virgin female albino rats and the therapy was started two months after carcinogen administration. The acute effect of DMBA on the uterine sensitivity was also assessed 24 h post-carcinogen. The uterotonic potentials of oxytocin and prostaglandin F2 alpha (PGF2 alpha) were markedly reduced in the control tumour-bearing group as compared to the normal one. Similarly, acute DMBA administration showed reduced uterine sensitivity to both agents. Treatment with either TAM or combined TAM/rHuIFN alpha 2b did not affect the uterine response to either oxytocin or PGF2 alpha, while rHuIFN alpha 2b increased the uterine sensitivity to oxytocin but not to PGF2 alpha. These data indicate that the carcinogenic agent per se and the presence of tumour reduce the contractile response in the rat uterus to oxytocic agents. Moreover, combined TAM/rHuIFN alpha 2b does not markedly affect the uterine sensitivity in DMBA-induced mammary carcinoma-bearing rats.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1980

Results with tamoxifen in advanced mammary carcinoma.

The results of a study with tamoxifen (TAM) (10 mg three times daily) in advanced breast cancer are reported. Of 44 patients, 24 showed a remission and 20 a progression. Of the 17 patients in whom an oestrogen receptor (ER) determination in tumour tissue had been carried out, 12 were receptor-positive (ER+) and five receptor-negative (ER-). Nine of the 12 ER+ cases (75%) responded to the treatment with TAM. Of the five ER- patients, one showed remission and four progression.

Bone Neoplasms↗

PubMed1998

Morphological and hemodynamic evaluations by means of transcranial power Doppler imaging in patients with severe head injury.

The following conditions of 17 patients with severe head injury (ages 9-76; mean 37:12 focal and 5 diffuse injuries) were evaluated during acute phase (1-14 days after injury, mean 5) by transcranial power Doppler imaging (PDI), a new color Doppler ultrasound technique: a) morphological changes via temporal window, b) hemodynamic changes in major intracranial/cervical arteries based on measured angle-corrected time-averaged mean (TAM)/ peak velocities and vessel diameter (Va), and calculated pulsatility indices (PI), vessel area (Va), and flow volume (Vf = TAM x Va). a) 1) Major trunks of intracranial vessels and circle of Willis and pathological changes in frontal/temporal lobes and midbrain were finely visualized. 2) Contusional hemorrhage and cerebral contusion demonstrated irregular hyper- and hypo-echoic lesions, respectively. 3) Delayed epidural hematoma showed a hyper-echoic band. b) 1) Decreased velocities, significant PI increase, and Va increase tendency were observed in intracranial arteries. 2) Increased velocities with Vf increase but no Va decrease indicated hyperemia rather than vasospasm. 3) Va in the intracranial vessels, however, tended to increase PDI appears useful in evaluating real-time and simultaneous morphological and hemodynamic information in pathogenesis and neurointensive care of patients with severe head injury.

Adolescent↗

PubMed1993

Action of estradiol and tamoxifen on the testis-inducing activity of the chick embryonic testis grafted to the female embryo.

The implantation of two testes from 13-day-old male chick donor embryos into the extra-embryonic celom of 3-day-old female embryos induces the masculinization of their ovaries up to a total and definitive inversion of their gonadal sex, i.e., the differentiation of testes in the female hosts. Pretreatment of the donors with estradiol (E2) between day 11 and 13 counteracts the testis-inducing activity of the implants, while co-treatment of donors with both tamoxifen (TAM) and E2 at the same stage restores the initially observed activity. The treatment of 3-day-old male donor embryos with E2 causes the differentiation of their left gonad into an ovotestis totally devoid of testis-inducing activity once grafted in the same conditions as above. An additional treatment with TAM of the grafted host embryos does not modify the results obtained when E2-treated male gonads are grafted to normal host embryos. This shows that the lack of testis-inducing activity exhibited by the E2-treated grafts can not be attributed to a protecting action of endogenous estrogens on the gonads of the host. On account of previous work showing the inhibition by E2 of the Müllero-regressive activity of the chick embryonic testis, our present results can be interpreted in terms of E2-down regulation of Anti-Müllerian Hormone (AMH or MIS), which appears to be a good candidate as testis-inducer. The relevance of our results to the phenomenon of gonad differentiation is discussed.

Animals↗

PubMed1986

The antiproliferative properties of tamoxifen and phenothiazines may be mediated by a unique histamine receptor (?H3) distinct from the calmodulin-binding site.

N,N-diethyl-2-[(4-phenylmethyl)-phenoxy]-ethanamine HCl (DPPE), a novel histamine antagonist (?H3), which selectively binds with high affinity to the antiestrogen-binding site (AEBS/?H3), inhibits the activity of calmodulin-dependent myosin light chain kinase (MLCK) only at concentrations greater than 1 mM, as opposed to tamoxifen (TAM), which has an IC50 = 4 microM in the same assay. This suggests that the antiestrogen-binding site is distinct from the site on calmodulin which binds TAM and phenothiazines. However, at an in vitro concentration of 1 X 10(-6) M, the antiproliferative effects of DPPE and several phenothiazines, which also compete for binding to AEBS/?H3, are about equal; this suggests that affinity for AEBS/?H3 rather than that for the calmodulin-binding site may correlate with clinically relevant antigrowth effects of these compounds.

Animals↗