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PubMed2002

4-Hydroxytamoxifen induces slight uncoupling of mitochondrial oxidative phosphorylation system in relation to the deleterious effects of tamoxifen.

The use of tamoxifen (TAM) has been questioned on the chemotherapy and chemoprevention of breast cancer due to several estrogen receptor-independent cytotoxic effects. As an alternative, its more active metabolite 4-hydroxytamoxifen (OHTAM) has been proposed with presumed lower side effects. In this work, the potential OHTAM toxicity on rat liver mitochondrial bioenergetics in relation to the multiple deleterious effects of TAM was evaluated. OHTAM, at concentrations lower than those putatively reached in tissues following the administration of TAM, does not induce significant perturbations on the respiratory control ratio (RCR), ADP/O, transmembrane potential (DeltaPsi), phosphorylative capacity and membrane integrity of mitochondria. However, at high concentrations, OHTAM depresses the DeltaPsi, RCR and ADP/O, affecting the phosphorylation efficiency, as also inferred from the DeltaPsi fluctuations and pH changes associated with ADP phosphorylation. Moreover, OHTAM, at concentrations that stimulate the rate of state 4 respiration in parallel to the decrease in the DeltaPsi and phosphorylation rate, causes mitochondrial swelling and stimulates both ATPase and citrate synthase activities. However, the OHTAM-observed effects, at high concentrations, are not significant relatively to the damaging effects promoted by TAM and suggest alterations to mitochondrial functions due to proton leak across the mitochondrial inner membrane.

Adenine Nucleotides↗
PubMed1985

The effect of vincular injury on the results of flexor tendon surgery in zone 2.

From a consecutive series of 82 fingers (69 patients) that sustained flexor tendon lacerations in zone 2, 47 fingers (39 patients) had the status of the vincular system determined during primary repair. The vincula were intact in 22 fingers and not intact in 25. Total active motion (TAM) after rehabilitation and before a reconstructive procedure, such as repair of a rupture, tenolysis, or grafting of a tendon, was the end point of the study. The overall mean TAM was 196 degrees. The mean TAM was 222 degrees for fingers with intact vincula and 176 degrees for fingers with vincula not intact (p less than 0.01). There were no statistical differences between the two groups regarding surgical results when the number of tendons injured per finger and sheath closure were analyzed. This study suggests that the integrity of the vincular system is a determinant of end result TAM and flexor tendon lacerations in zone 2.

Adolescent↗
PubMed2002

Breast-conserving therapy consisting of wide excision, axillary dissection, and radiotherapy for early-stage breast cancer: the experience of the National Shikoku Cancer Center.

Four hundred and forty-eight breasts of 443 female patients were treated with breast-conserving therapy (BCT) consisting of wide excision, axillary dissection, and radiotherapy for early-stage breast cancer at the National Shikoku Cancer Center between July 1989 and December 1999. The average age at operation was 48.7 years, and the mean tumor size by palpation was 1.9 cm. Three hundred and twenty cases (71.4%) were pathologically node-negative. During a median follow-up period of 53 months, 13 patients developed local recurrence. The 5-year overall survival and local recurrence rate registered 94.5% and 3.0%, respectively. Age at operation (35 years or younger vs. 36 years or older; P = 0.0184), pathological lymph node status (P = 0.0261), adjuvant chemotherapy (P = 0.0198), and the combination of estrogen receptor (ER) status and adjuvant tamoxifen (TAM) (ER+ and TAM+ vs. ER- or TAM-; P = 0.0136) were statistically significantly associated with local recurrence. Histological margin status associated with local recurrence was marginally significantly (P = 0.0751). The results of multivariate analysis revealed that age at operation, pathological lymph node status, the combination of ER status and adjuvant TAM, and histological margin status were statistically independent predictors for local recurrence. In conclusion, BCT consisting of wide excision, axillary dissection and radiotherapy is useful and effective for patients with early-stage breast cancer.

Academic Medical Centers↗
PubMed2001

Effects of chronic estradiol benzoate treatment on amygdala kindled seizures in male rats.

In the female species, effect of estrogens on seizure activity is well documented, but not much is known on the effect of this ubiquitous steroid hormone on the seizure activity of the male species. In the present study, fully kindled male rats were treated with various doses (10, 30 and 50 microg/kg, i.p.) of estradiol benzoate (EB) daily, and kindled seizure parameters such as seizure stage (SS), after discharge duration (ADD) and stage 5 duration (S(5)D) were recorded at various times (0.25, 3 h and every 24 h for 96 h) after the first of daily EB treatments. While the 10-microg/kg dose of EB failed to produce any significant effect, the 30-microg/kg dose induced a triphasic effect on seizure parameters. An initially rapid increment of ADD (after 0.25 h), followed by significant decrease of all parameters at 48 h and later a significant increase in S(5)D was observed 96 h after the first of daily EB treatments. The 50-microg/kg dose of EB produced almost a similar but less marked pattern of effects. Pre-treatment with a 3-mg/kg dose of tamoxifen citrate (TAM), not only blocked the EB (30 microg/kg) effects till 72 h but also reduced the ADD and S(5)D significantly after 0.25 h, when compared to its control group. While pre-treatment with the 10-mg/kg dose of TAM only blocked the inhibitory effects of EB 48 h after the first of daily EB treatments. Administration of the latter dose of TAM alone induced a profile similar to EB treatment. These results may suggest that in male rats, estradiol treatment can both potentiate and attenuate kindled seizure parameters in a time dependent manner, and the stimulatory effects can not be blocked by TAM pre-treatment.

Amygdala↗
PubMed2003

Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy.

For treatment of early breast cancer in older women, little evidence is available from randomised trials. We conducted a randomised trial comparing modified radical mastectomy (MRM) with tamoxifen (TAM) as the sole initial therapy in 164 patients aged >/=70 years with operable breast cancer. 82 were treated by MRM and 82 with TAM. Survival curves were estimated using the Kaplan-Meier method: multivariate analyses were performed using the Cox's proportional hazards model. Endpoints included survival, time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. After a median follow-up of approximately 10 years, there was a significantly decreased time to progression in the TAM only group (logrank P<0.0001) and significantly shorter time to local progression within the TAM group (logrank P<0.0001). Overall survival of the two groups was similar. The results indicate that tamoxifen alone leads to an unacceptably high rate of local progression or relapse.

Aged↗
PubMed1993

Effect of endocrine therapy on growth of T61 human breast cancer xenografts is directly correlated to a specific down-regulation of insulin-like growth factor II (IGF-II).

Insulin-like growth factors I and II (IGF-I and IGF-II) are potent mitogens for some human breast cancer cell lines, and expression of IGF-II mRNA in the oestrogen receptor-positive (ER+) and oestradiol (E2) stimulated human breast cancer cell line T47D is increased by E2, suggesting a role for IGF-II in the mitogenic response to E2. Very little information is available from the literature on the relation between growth inhibition by endocrine therapy and cellular production of IGF-II. Here we report on the effect of E2 and tamoxifen (TAM) on IGF-II mRNA and protein expression in the ER+T61 human breast cancer xenograft. Growth of the T61 tumour is inhibited by treatment with E2 and TAM. Ribonuclease (RNAse) protection assays with human- and mouse-specific IGF-II antisense probes were used to study the regulation of IGF-II mRNA by E2 and TAM in the tumour. IGF-II protein expression was studied by radioimmunoassay. Untreated T61 tumours have a high baseline expression of IGF-II mRNA. TAM treatment of T61 tumours, which results in inhibition of tumour growth without tumour regression, reduced IGF-II mRNA expression approximately 10-fold after 48 h of treatment. E2 treatment of T61 tumours, which results in tumour regression, was accompanied by a more pronounced decrease in IGF-II mRNA expression in the tumour cells; 96 h after initiation of E2 treatment, there was almost no detectable IGF-II mRNA. Analyses of IGF-II protein showed that both treatments significantly reduced the concentration of IGF-II protein in the tumours. This down-regulation was found to be specific for IGF-II, since analyses of the effect of E2 on the expression of IGF-I mRNA, 36B4 mRNA, transforming growth factor alpha(TGF-alpha) mRNA, and epidermal growth factor (EGF) receptor mRNA in T61 tumours did not reveal any down-regulation. To further study the relation between inhibition of tumour growth and down-regulation of IGF-II, we exposed T61 tumours to a monoclonal antibody, alpha-IR3, which abolishes the physiological effect of IGF-I and IGF-II by blocking the binding of both growth factors to the type I IGF receptor. Treatment with alpha-IR3 resulted in inhibition of tumour growth during treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Possible deleterious effect of tamoxifen in premenopausal women with locoregional recurrence of breast cancer.

Tamoxifen (TAM) treatment following isolated locoregional recurrence of breast cancer significantly increases 5-year disease-free survival rates compared with observation alone in potentially hormone-responsive patients [J Clin Oncol 1994, 12, 2071-2077]. The treatment outcome was re-analysed by menopausal status (stratification factor) in 35 premenopausal and in 132 postmenopausal patients. Disease progression was highly reduced by tamoxifen in the postmenopausal group and was similar to control in the premenopausal group. However, the 5-year cumulative incidence analysis of the type of first failure showed TAM to be associated with increased incidence of distant metastases (P = 0.01) in premenopausal patients. TAM reduced local progression (P = 0.40) in premenopausal and both types of failure (P = 0.16 and P = 0.001, respectively) in postmenopausal patients. Administration of TAM was associated with a decrease of 5-year overall survival from 90 +/- 7% to 60 +/- 14% in premenopausal patients. Although cautious interpretation of these results is highly recommended due to the small patient numbers and the retrospective subset analyses, these findings might be worthy of further investigation in larger trials. Prospective randomised studies to test hormonal treatment outcome by menopausal status should be encouraged in breast cancer.

Adult↗
PubMed2002

Temporal effect of tamoxifen on cytochrome P450 side chain cleavage gene expression and steroid concentration in adult male rats.

Adult male rats when treated with 0.4 mg tamoxifen (tam)/kg per day for 90 days show reduced circulating testosterone (T) and LH. The present study was designed to have an in depth understanding of tam induced androgen reduction in adult male rats. Adult male rats were orally administered 0.4 mg tam/kg per day for 30, 60 or 90 days and the temporal effects on intratesticular concentrations of pregnenolone (P(5)), progesterone (P(4)), T, 5 alpha-dihydrotestosterone (5 alpha-DHT) and estradiol (E(2)) were estimated. Control group rats were fed saline. Serum hormonal profile of LH, FSH, T and E(2) was also followed on these days. Testicular levels of cytochrome P450 scc mRNA transcripts on 30, 60 and 90 days of treatment with the same dose were quantitated by biplex RT-PCR using beta Actin as internal control followed by analysis using GelPro Analysis software.A significant reduction in intratesticular P(5), P(4), T, 5 alpha-DHT and E(2) was observed from day 30 of treatment. The P450 scc gene expression in the testis was reduced during treatment period from day 60 of treatment. This study demonstrates for the first time that tam reduces testicular pregnenolone biosynthesis through an effect on cholesterol transport and downregulation of P450 scc gene expression. In confirmation of the observed estrogenic effects of tam in this study, it is suggested that E(2) may have a role in cholesterol transport and testicular pregnenolone biosynthesis at the level of cytochrome P450 scc as shown by us.

Administration, Oral↗
PubMed1998

Tamoxifen up-regulates oestrogen receptor-alpha, c-fos and glyceraldehyde 3-phosphate-dehydrogenase mRNAs in ovine endometrium.

Tamoxifen, the antiestrogen most widely used in medicine, was tested in ewes to determine whether it antagonizes oestradiol up-regulation of ER, PR, and other genes reported to be oestrogen-modulated (c-fos, oxytocin receptor (OTR), glyceraldehyde phosphate dehydrogenase (GAPDH), and apolipoprotein AI (apo AI)) in endometrium and liver. Ovariectomized ewes (n = 6 ewes per group) were injected with 20 mg tamoxifen (Tam) 24 h prior to tissue collection, 50 microg oestradiol (E2) 18 h prior to tissue collection, both drugs (T + E2) or drug vehicle (Con). E2 treatment resulted in 857 +/- 93 pg oestradiol/g endometrium. Gross uterine characteristics of Tam- and T + E2-treated ewes were intermediate to those in Con and E2 groups. In endometrium, Tam treatment mimicked E2 treatment in up-regulating ER, c-fos, and GAPDH mRNAs two- or three-fold. However, neither E2 nor Tam treatments affected concentrations of OTR mRNA in endometrium, or ER, c-fos, GAPDH, OTR and apo AI mRNAs in liver. Like oestradiol, tamoxifen stabilized endometrial ER mRNA more than 3-fold in endometrial explants cultured with the transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). Thus, tamoxifen acts as an oestradiol agonist in ovine endometrium and shares a posttranscriptional mechanism with oestradiol in the up-regulation of ER gene expression.

Animals↗
PubMed2002

Effect of dye aggregation on triarylmethane-mediated photoinduced damage of hexokinase and DNA.

The observation that enhanced mitochondrial membrane potential is a prevalent cancer cell phenotype has provided the conceptual basis for the development of mitochondrial targeting as a novel therapeutic strategy for both chemo- and photochemotherapy of neoplastic diseases. Cationic triarylmethane (TAM(+)) dyes represent a series of photosensitizers whose phototoxic effects develop at least in part at the mitochondrial level. In this report we describe how the molecular structure of four representative TAM(+) dyes (Crystal Violet, Ethyl Violet, Victoria blue R, and Victoria pure blue BO) affects their efficiency as mediators of the photoinduced inactivation of two model mitochondrial targets, hexokinase (HK) and DNA. Our results have indicated that TAM(+) dyes efficiently bind to HK and DNA in aqueous media both as dye monomers and aggregates, with the degree of aggregation increasing with increasing the lipophilic character of the photosensitizer. The efficiency with which HK and DNA are damaged upon 532 nm photolysis of biopolymer-TAM(+) complexes was found to decrease upon increasing the degree of dye aggregation over these macromolecular templates. Comparative experiments carried out both in water and in D(2)O, and in air-equilibrated and nitrogen-purged samples have also indicated that, at least when Crystal Violet is used as the photosensitizer, the mechanism of macromolecular damage does not require the involvement of molecular oxygen to operate. This finding makes Crystal Violet a potential candidate for use in photochemotherapy of hypoxic or poorly perfused tumor areas.

Coloring Agents↗
PubMed2002

Tumor-associated macrophages: a molecular perspective.

The "macrophage balance hypothesis" was proposed in the early 1990s to depict the complex relationship that tumor-associated macrophages (TAM) have with the neoplastic cells of the tumor. TAM represent a prominent component of the mononuclear leukocyte population of solid tumors, which displays an ambivalent relationship with tumors. They originate in the circulation and are recruited to the tumor site by tumor-derived attractants such as chemokines and interact with the tumor cells and preferentially localize at the tumor-host tissue interface, in regions often associated with low oxygen tensions. The tumor microenvironment, including cytokines and hypoxia, regulates the localization and function of TAM. Emerging evidence starts to define the molecular basis for the peculiar functional phenotype of TAM and identifies possible therapeutic targets.

Animals↗
PubMed2001

Phase III randomized trial of toremifene vs tamoxifen in hormonodependant advanced breast cancer.

PURPOSE: Efficacy and safety of toremifene (TOR) 60 mgs/dayly/o.r. was compared with tamoxifen (TAM) 40 mgs/dayly/o.r. in a group of postmenopausal women with advanced breast cancer, without previous systemic therapy for advanced breast cancer. MATERIAL AND METHODS: The study was a prospective double-blind randomized trial. All treated patients presented with positive estrogen receptors. Main end points were response rates, toxicity profile analysis, time to progression and survival. WHO and ECOG criteria were employed for response evaluation while toxicity was assesed according to WHO guidelines. Curves were constructed by means of Kaplan-Meier methodology and were compared by means of log-rank test. RESULTS: From January 1996 to January 1999 a total of 217 patients were included in the study (106 in the TOR branch and 111 in the TAM arm). Both groups of patients were homogeneous regarding the main prognostic factors. A response rate of 64% (68/106) was observed in the TOR group as compared with a 52% (58/111) in the TAM group. Median times to progression and overall survival were not significantly different. A lower incidence of undesirable effects was apreciated in the TOR arm. CONCLUSIONS: Our data suggest that TOR is an efficient and well-tolerated agent for the therapy of postmenopausal women with hormonal positive receptors advanced breast cancer, and must be considered an alternative to TAM as first line therapy for ER+ advanced breast cancer patients and as well as an adjuvant treatment.

Aged↗
PubMed1997

Activation of signal transduction kinases by tamoxifen.

PURPOSE: To study the signal transduction mechanisms of tamoxifen via the activation of MAPKs, JNK and ERK in order to understand its regulation of gene expression. METHODS: The effects of tamoxifen (TAM) on the activation of serine/threonine mitogen-activated protein kinase (MAPK, p42/ERK2) and the stress-activated protein kinases (p46 SAPK or c-Jun N-terminal kinase, JNK1) were evaluated using a human cervical epitheloid carcinoma HeLa cell line. RESULTS: TAM activated both JNK1 and ERK2 activities in a time- and dose-dependent manner in HeLa cells. The activation of JNK1 was enhanced when the cells were pretreated with prooxidant H2O2. CONCLUSIONS: These studies show that TAM activates the signal transduction kinases, JNK1 and ERK2, which may play important roles in the regulation of gene expression by TAM.

Antineoplastic Agents, Hormonal↗
PubMed2002

[Breast carcinoma: value of adjuvant therapy after mastectomy? Overview of personal results over > or = 20 years].

Analysis of 626 consecutive locoregional postoperative irradiated patients after mastectomy. 49.5% (310/626) were without further therapies, 32.8% (205/626) received TAM and 17.7% (111/626) an adjuvant chemotherapy +/- TAM. All tumours were classified on the basis of the pathologic-anatomical spreading. Median age 59 (25-91) years, follow-up 180 (60-265) months. Local relapses 7.1%, distant metastases 40.4%, death as consequence of breast cancer 35.6%, in 20.3% death of other causes. Cause specific survival (CSS) by negative axilla in 76%, by 1 to 3 LN+ metastases in 55% and by > or = LN+ in 30%. On the basis of the final results, lymphnode status, vascular invasion and initial tumor size have been the most important risk factors of prognostic relevance. Their rate of local relapses have been twice to six times as high, the distant metastasis 1.5 to 2 times more frequent. Immense differences too in comparing the CSS after 20 years: high risk collective 26 to 47%, low risk 65 to 72%. No statistical difference has shown in the low risk collective between the therapy groups. As referred back to the initial axillary status, 39.6% (248/626) have been without positive LN at the time of mastectomy. 76.2% (189/248) have remaind without distant metastases (DM), in 78.4% (149/190) without adjuvant therapy after locoregional irradiation. In 60.4% (378/626) the axilla was attacked. 48.7% (184/378) remained without distant metastases. 19.6% (36/184) with chemotherapy, 49.4% (91/184) with TAM and 31% (57/184) without supplemented systemic therapies. With 1 to 3 LN+ 58.4% (108/185) neither clinical nor radiological dissemination proven. It may be due to the efficiency of chemotherapy and TAM that only in 38.2% (13/34) respectively in 34.3% (23/67) distant metastases have been proven. In contrary after > or = 4 LN+ the chemotherapy-group has had 76.2% (48/63) and by combination with vascular invasion 85.2% (23/27) distant metastases. An opposite effect cannot be excluded. A positive axilla may but doesn't have to be a harbinger of tumor generalisation, since on third has remained without distant metastases despite of the lack of adjuvant therapies after locoregional irradiation. Is it possible a consequence of the irradiation too? No side effects of importance: Absence of plexopathies, no cardiotoxicity, 0.8% rib-necrosis after high dose irradiation as a consequence of R1-resections. There are no reasons for a renunciation of postmastectomy irradiation because of its secondary effects.

Adult↗
PubMed2003

Processing similarity does not improve metamemory: evidence against transfer-appropriate monitoring.

The transfer-appropriate monitoring (TAM) hypothesis of metamemory predicts that judgment of learning (JOL) accuracy should improve when conditions during JOLs closely match conditions of the memory test. The authors devised 5 types of delayed JOLs for paired associates and varied them along with the type of memory test (cued recall or recognition). If the TAM hypothesis is correct, JOL and test type should interact to influence metamemory. Contrary to TAM, metamemory accuracy did not improve when JOL and test conditions matched but instead tended to vary according to whether the answer was apparent at time of JOL. Memory test scores and JOL magnitude were both greater when the correct target was evident during JOLs. Overall, the results are largely consistent with a monitoring retrieval view of delayed JOLs and do not support TAM as a viable account of JOL accuracy.

Attention↗
PubMed1992

Human tumour-associated macrophages are capable of bone resorption.

Cellular mechanisms of bone resorption associated with skeletal metastasis are poorly understood. Human tumour-associated macrophages (TAMs) isolated from primary lung carcinomas were incubated on bone slices where they formed resorption lacunae after 14 days co-culture with a mouse marrow-derived stromal cell line (ST2) with added 1 alpha, 25-dihydroxy Vitamin D3 and dexamethasone. These co-cultures were associated with the formation of increased numbers of tartrate resistant acid phosphatase positive mononuclear and multinucleated cells. Similar cocultures of ST2 cells with normal alveolar macrophages did not result in lacunar resorption. Both in the presence and absence of ST2 cells, TAMs and normal alveolar macrophages produced roughening of the bone surface with exposure of mineralised collagen fibres. TAMs are capable of both low-grade surface resorption and high-grade lacunar resorption of bone, and a specific interaction with stromal cells is necessary for the latter to occur. TAMs may thus directly contribute to the bone resorption associated with skeletal metastasis.

Bone Resorption↗
PubMed1994

Positive effect of tamoxifen as part of adjuvant chemo-endocrine therapy for breast cancer. Hokkaido Adjuvant Chemo-Endocrine Therapy for Breast Cancer Study Group.

A prospective randomised multicentre clinical study was undertaken for 2 years and 3 months from November 1982, with the aim of examining the significance of using a combination of ftorafur (FT) and tamoxifen (TAM) for post-operative adjuvant therapy of breast cancer. Patients had either stage II or stage IIIa disease, were age 75 or below and had undergone radical mastectomy. Patients were divided into two groups and received one of the following treatment protocols: treatment A, intravenous administration of doxorubicin (DOX), 20 mg on the day of surgery and 10 mg the next day, followed by oral FT 50 mg day-1 for 2 years from the 14th day; treatment B, the same pattern of DOX administration for the first 2 days, followed by a combined therapy of FT and TAM 20 mg day-1 for 2 years. The number of patients was 546 (treatment A 274 and treatment B 272), of whom 34 (6%) were ineligible. The remaining 512 patients (treatment A 254 and treatment B 258) were followed up for 5 years for analysis. Significantly higher 5 year disease-free rate and 5 year survival rates were observed with treatment B compared with treatment A. When seen in terms of background factors, node-positive patients appeared to derive more benefit from tamoxifen than node-negative patients, but the oestrogen receptor-negative and premenopausal subgroups appeared to derive about the same benefit as those who were oestrogen receptor positive and post-menopausal. Indeed, survival in the premenopausal group was significantly better with tamoxifen (P = 0.04). No increase in side-effects was seen by combining TAM with FT. The study results demonstrate that concomitant administration of FT and TAM is better than FT alone for post-operative adjuvant therapy for breast cancer.

Adult↗
PubMed1997

Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis.

The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.

Antineoplastic Combined Chemotherapy Protocols↗