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PubMed2006

Catechin prevents tamoxifen-induced oxidative stress and biochemical perturbations in mice.

Natural antioxidants like catechin are now known to have a modulatory role on physiological functions and biotransformation reactions involved in the detoxification process, thereby affording protection from toxic metabolic actions of xenobiotics. Reactive oxygen intermediates have been demonstrated to play an etiological role in anticancer drug-induced toxicity. This study was performed to explore the modulatory and protective effect of catechin on the toxicity of an anticancer drug, tamoxifen (TAM) with special reference to protection against disruption of glutathione metabolizing and antioxidant enzymes. TAM treatment resulted in a significant increase in the lipid peroxidation (LPO), H(2)O(2) generation and protein carbonyl (PC) contents in the liver and kidney as compared to controls while catechin+TAM-treated group showed significant decrease in LPO levels, H(2)O(2) generation and PC contents in liver and kidney when compared with TAM-treated group. Non-enzymatic antioxidants like reduced glutathione (GSH) and low molecular antioxidants like ascorbic acid (AsA) also showed normalcy due to exogenous catechin administration. Catechin pre-treatment showed restoration in the level of cytochrome P450 (CYP) content and in the activities of glutathione metabolizing enzymes, viz., glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and other antioxidant enzymes such as, glucose-6-phosphate dehydrogenase (G6-PD), catalase (CAT) and superoxide dismutase (SOD) in both liver and kidney when compared to TAM-treated animals. The results of the study show that catechin supplementation might be helpful in abrogation of TAM toxicity during chemotherapy. Additionally, it makes it a prophylactic and preventive agent of anticancer drug-induced oxidative stress.

Animals↗
PubMed2001

Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted two sequential randomized clinical trials to aid in resolving uncertainty about the treatment of women with small, localized, mammographically detected ductal carcinoma in situ (DCIS). After removal of the tumor and normal breast tissue so that specimen margins were histologically tumor-free (lumpectomy), 818 patients in the B-17 trial were randomly assigned to receive either radiation therapy to the ipsilateral breast or no radiation therapy. B-24, the second study, which involved 1,804 women, tested the hypothesis that, in DCIS patients with or without positive tumor specimen margins, lumpectomy, radiation, and tamoxifen (TAM) would be more effective than lumpectomy, radiation, and placebo in preventing invasive and noninvasive ipsilateral breast tumor recurrences (IBTRs), contralateral breast tumors (CBTs), and tumors at metastatic sites. The findings in this report continue to demonstrate through 12 years of follow-up that radiation after lumpectomy reduces the incidence rate of all IBTRs by 58%. They also demonstrate that the administration of TAM after lumpectomy and radiation therapy results in a significant decrease in the rate of all breast cancer events, particularly in invasive cancer. The findings from the B-17 and B-24 studies are related to those from the NSABP prevention (P-1) trial, which demonstrated a 50% reduction in the risk of invasive cancer in women with a history of atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS) and a reduction in the incidence of both DCIS and LCIS in women without a history of those tumors. The B-17 findings demonstrated that patients treated with lumpectomy alone were at greater risk for invasive cancer than were women in P-1 who had a history of ADH or LCIS and who received no radiation therapy or TAM. Although women who received radiation benefited from that therapy, they remained at higher risk for invasive cancer than women in P-1 who had a history of LCIS and who received placebo or TAM. Thus, if it is accepted from the P-1 findings that women at increased risk for invasive cancer are candidates for an intervention such as TAM, then it would seem that women with a history of DCIS should also be considered for such therapy in addition to radiation therapy. That statement does not imply that, as a result of the findings presented here, all DCIS patients should receive radiation and TAM. It does suggest, however, that, in the treatment of DCIS, the appropriate use of current and better therapeutic agents that become available could diminish the significance of breast cancer as a public health problem.

Antineoplastic Agents↗
PubMed1996

Tamoxifen synergizes the antiproliferative effect of cisplatin in human ovarian cancer cells: enhancement of DNA platination as a possible mechanism.

We investigated the chemosensitizing activity of tamoxifen (TAM) on estrogen receptor negative ovarian cancer cell lines sensitive (A2780 WT) and resistant to cisplatin (CP) (A2780 CP3). Our results showed that the treatment of both cell lines with the association TAM + CP (concentration range 0.01-1 microN and 0.1-1 microgram/ml, respectively) results in a synergistic antiproliferative activity and a complete reversal of the acquired CP-resistant phenotype. We demonstrated that in A2780 cells the addition of TAM to CP treatment is able to significantly enhance at every tested CP dose (P < 0.001) the amount of platinum (Pt) bound to the DNA. Since Pt-DNA levels in the genome are clearly related to the growth inhibitory effect of CP (correlation value = 0.97, P < 0.001) in our experimental model, we hypothesized that TAM could act synergistically with CP and overcome the acquired CP-resistance by enhancing Pt binding to the DNA. We suggest that, from a clinical point of view, TAM may be usefully included in CP-based chemotherapy regimens for ovarian cancer patients since plasma concentrations of the drug capable of in vitro CP resistance modulation are achievable in vivo. A prospective clinical trial to verify the clinical usefulness of combined TAM + CP treatment in ovarian cancer patients refractory to prior Pt-based chemotherapy is now underway in our department.

Antineoplastic Agents↗
PubMed2003

Prospective comparison of breast pain in patients participating in a randomized trial of breast-conserving surgery and tamoxifen with or without radiotherapy.

PURPOSE: To determine whether breast pain affects quality of life (QOL) after breast-conserving surgery and tamoxifen (TAM) with or without adjuvant breast radiotherapy (RT). METHODS AND MATERIALS: A randomized clinical trial was carried out at the Princess Margaret Hospital between 1992 and 2000 to evaluate the need for breast RT in addition to TAM in women >or=50 years treated with breast-conserving surgery for T1-T2N0 breast cancer. A companion study to assess breast pain was carried out during the last 2 years of the randomized clinical trial. The short-form McGill Pain Questionnaire (SF-MPQ), the European Organization for Research and Treatment of Cancer (EORTC) QOL (QLQ-C30) and EORTC breast cancer module (QLQ-BR23) questionnaires were completed by patients within 1 week of randomization in the randomized clinical trial (baseline) and at 3, 6, and 12 months. RESULTS: Eighty-six patients participated in the breast pain study; 41 received RT plus TAM and 45 received TAM alone. The median age was 70 years (range 51-80). The baseline pain and QOL scores were similar for the two groups. No significant difference was found between the two groups for each scale of the QLQ-C30 and QLQ-BR23 questionnaires at 3, 6, or 12 months (p >0.100), except that at 12 months, the score for role function (QLQ-C30) was higher in the RT plus TAM group than in the RT-only group (p = 0.02). At 3 months, the difference between the mean scores for the SF-MPQ was 0.553 (p = 0.47). At 12 months, the pain scores had decreased in both groups; the difference was 0.199 (p = 0.71). The number of breast operations or surgical complications did not correlate with breast pain in either group. Acute RT toxicity scores did not correlate with breast pain or QOL scores at 12 months. CONCLUSION: These results suggest that breast RT does not significantly contribute to breast pain or adversely impact the QOL up to 12 months after treatment in postmenopausal patients with node-negative breast cancer who take TAM.

Aged↗
PubMed2001

Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis.

4-Hydroxytamoxifen (OHTAM) is the most active metabolite of the widely prescribed anticancer drug tamoxifen (TAM) used in breast cancer therapy. This work describes the effects of OHTAM on isolated human erythrocytes, using standardized test conditions, to check for a putative contribution to the TAM-induced hemolysis and to study basic mechanisms involved in the interaction of OHTAM with cell membranes. Incubation of isolated human erythrocytes with relatively high concentrations of OHTAM results in a concentration-dependent hemolysis, its hemolytic effect being about one-third of that induced by TAM. OHTAM-induced hemolysis is prevented by either alpha-tocopherol (alpha-T) or alpha-tocopherol acetate (alpha-TAc) and it occurs in the absence of oxygen consumption and hemoglobin oxidation, ruling out the oxidative damage of erythrocytes. However, OHTAM remarkably increases the osmotic fragility of erythrocytes, increasing the susceptibility of erythrocytes to hypotonic lysis. Additionally, the hemoglobin release induced by OHTAM is preceded by a rapid efflux of intracellular K(+). Therefore, our data suggest that OHTAM-induced hemolysis does not contribute to TAM-induced hemolytic anemia and it is a much weaker toxic drug as compared with TAM. Moreover, at variance with the membrane disrupting effects of TAM, OHTAM promotes perturbation of the membrane's backbone region due to its strong binding to proteins with consequent formation of membrane paths of permeability to small solutes and retention of large solutes like hemoglobin, followed by osmotic swelling and cell lysis. The prevention of OHTAM-induced hemolysis by alpha-T and alpha-TAc is probably committed to the permeability sealing resulting from structural stabilization of membrane.

Adult↗
PubMed1999

Tamoxifen in high-risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy. Report from the Danish Breast Cancer co-operative Group DBCG 82B Trial.

Following modified radical mastectomy, pre- and perimenopausal (amenorrhoea for < 5 years) patients with stage II or III breast cancer received CMF (cyclophosphamide 600, methotrexate 40, 5-fluorouracil 600 mg/m2 intravenously (i.v.) every 4 weeks, 9 cycles). The effect on recurrence-free survival (RFS) and overall survival (OS) of the addition of adjuvant tamoxifen (TAM) to adjuvant chemotherapy was examined by randomisation either to no additional treatment (n = 314), or concurrently TAM 30 mg daily for 1 year (n = 320). 40% had positive, 12% negative and 48% unknown receptor status. One year after surgery 21% versus 35% (CMF + TAM versus CMF) were still menstruating (P < 0.01). With a median follow-up of 12.2 years there was no difference in RFS (10-year RFS 34% versus 35%, P = 0.81) or OS (45% versus 46%, P = 0.73). In a Cox proportional hazards model, tumour size, number of metastatic lymph nodes, frequency of metastatic nodes in relation to total number of nodes removed, degree of anaplasia, age, and menostasia within the first year after operation were significant independent prognostic factors for RFS, and the same factors except age for OS. No significant interactions with TAM were seen. Thus, in this group of pre- and perimenopausal high-risk early breast cancer patients with heterogeneous receptor status given CMF i.v., concurrent TAM for 1 year did not improve the outcome. These results do not exclude that receptor positive patients may benefit from adjuvant TAM for longer periods given sequentially to chemotherapy.

Adult↗
PubMed2004

Antiestrogen binding site and estrogen receptor mediate uptake and distribution of 4-hydroxytamoxifen-targeted doxorubicin-formaldehyde conjugate in breast cancer cells.

The anthracycline antitumor drug, doxorubicin (DOX), has long been used as a broad spectrum chemotherapeutic. The literature now documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline-formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. We have recently reported the design, synthesis, and preliminary evaluation of a doxorubicin-formaldehyde conjugate targeted, via 4-hydroxytamoxifen, to the estrogen receptor (ER) and antiestrogen binding site (AEBS), which are commonly present in breast cancer cells. The lead targeted doxorubicin-formaldehyde conjugate, called DOX-TEG-TAM, was found to possess superior cell growth inhibition characteristics relative to clinical doxorubicin and an untargeted control conjugate, especially in ER-negative, multidrug resistant MCF-7/Adr cells. The enhanced activity in the absence of estrogen receptor raised the possibility that targeting was also mediated via AEBS. Fluorescence microscopy of an ER-negative, AEBS-positive cell line as a function of time showed initial DOX-TEG-TAM localization in cytosol, in contrast to initial DOX and untargeted doxorubicin-formaldehyde conjugate localization in the nucleus. DOX-TEG-TAM was taken up by four AEBS-positive cell lines to a greater extent than doxorubicin and an untargeted doxorubicin-formaldehyde conjugate. Of the four cell lines, three were ER negative. DOX-TEG-TAM uptake was inhibited in a dose-dependent manner by the presence of a competing AEBS ligand. DOX-TEG-TAM retains 60% of the affinity of 4-hydroxytamoxifen for AEBS. DOX-TEG-TAM was also taken up by the AEBS-negative, ER-positive cancer cell line Rtx-6; with these cells uptake was inhibited in a dose-dependent manner by the ER ligand, estradiol. The data support the hypothesis that uptake of 4-hydroxytamoxifen targeted doxorubicin-formaldehyde conjugate is mediated by both the antiestrogen binding site and estrogen receptor.

Antineoplastic Agents↗
PubMed1996

Synthesis, biodistribution, and estrogen receptor scintigraphy of indium-111-diethylenetriaminepentaacetic acid-tamoxifen analogue.

This study was aimed at developing a hydrophilic diethylenetriaminepentaacetic acid-tamoxifen (DTPA-Tam) analogue for use in imaging estrogen receptor positive (ER+) lesions. In rat uterine cytosol, the IC50 of DTPA-Tam conjugate was 1 microM and of tamoxifen, 2 microM. Biodistribution, autoradiography, and radionuclide imaging of 111In-DTPA-Tam in breast-tumor-bearing rats showed that tumor-to-tissue ratios increased steadily between 30 min and 48 h. The in vivo response of MCF-7 breast cancer xenografts to tamoxifen and DTPA-Tam in nude mice demonstrated that DTPA-Tam could reduce tumor growth rate. These results indicate that DTPA-Tam, a new hydrophilic ER+ ligand, might be useful in diagnosing ER+ lesions.

Animals↗
PubMed2006

Quantitative profiling of drug-associated proteomic alterations by combined 2-nitrobenzenesulfenyl chloride (NBS) isotope labeling and 2DE/MS identification.

The identification of drug-responsive biomarkers in complex protein mixtures is an important goal of quantitative proteomics. Here, we describe a novel approach for identifying such drug-induced protein alterations, which combines 2-nitrobenzenesulfenyl chloride (NBS) tryptophan labeling with two-dimensional gel electrophoresis (2DE)/mass spectrometry (MS). Lysates from drug-treated and control samples are labeled with light or heavy NBS moiety and separated on a common 2DE gel, and protein alterations are identified by MS through the differential intensity of paired NBS peptide peaks. Using NBS/2DE/MS, we profiled the proteomic alterations induced by tamoxifen (TAM) in the estrogen receptor (ER) positive MCF-7 breast cancer cell line. Of 88 protein spots that significantly changed upon TAM treatment, 44 spots representing 23 distinct protein species were successfully identified with NBS-paired peptides. Of these 23 TAM-altered proteins, 16 (70%) have not been previously associated with TAM or ER activity. We found the NBS labeling procedure to be both technically and biologically reproducible, and the NBS/2DE/MS alterations exhibited good concordance with conventional 2DE differential protein quantitation, with discrepancies largely due to the comigration of distinct proteins in the regular 2DE gels. To validate the NBS/2DE/MS results, we used immunoblotting to confirm GRP78, CK19, and PA2G4 as bona fide TAM-regulated proteins. Furthermore, we demonstrate that PA2G4 expression can serve as a novel prognostic factor for disease-free survival in two independent breast cancer patient cohorts. To our knowledge, this is the first report describing the proteomic changes in breast cancer cells induced by TAM, the most commonly used selective estrogen receptor modulator (SERM). Our results indicate that NBS/2DE/MS may represent a more reliable approach for cellular protein quantitation than conventional 2DE approaches.

Cell Line, Tumor↗
PubMed2001

Mechanisms of tamoxifen-induced apoptosis.

Tamoxifen (TAM) has been used in the treatment of breast cancer for over a decade. The observed clinical efficacy of TAM has been attributed to both growth arrest and induction of apoptosis within the breast cancer cells. Although the primary mechanism of action of TAM is believed to be through the inhibition of estrogen receptor (ER), research over the years has indicated that additional, non-ER-mediated mechanisms exist. These include modulation of signaling proteins such as protein kinase C (PKC), calmodulin, transforming growth factor-beta (TGFbeta), and the protooncogene c-myc. Recent studies, including those from our laboratory, have implicated the role of caspases and mitogen-activated protein kinases (MAPK), including c-Jun N-terminal kinase (JNK) and p38 in TAM-induced apoptotic signaling. Oxidative stress, mitochondrial permeability transition (MPT), ceramide generation as well as changes in cell membrane fluidity may also play important roles in TAM-induced apoptosis. These various signaling pathways underlying TAM-induced apoptosis will be reviewed in this article.

Animals↗
PubMed2003

Lignans and tamoxifen, alone or in combination, reduce human breast cancer cell adhesion, invasion and migration in vitro.

Flaxseed has been shown to reduce the metastasis of estrogen receptor negative (ER-) human breast cancer in nude mice. This study determined whether enterodiol (ED) and enterolactone (EL), metabolites of plant lignans exceptionally rich in flaxseed, and tamoxifen (TAM), alone or in combination, can influence the various steps of metastasis, that is, breast cancer cell adhesion, invasion and migration, of two ER- human breast cancer cell lines, MDA-MB-435 and MDA-MB-231. The inhibition by ED, EL or TAM (1-5 microM) of cell adhesion to Matrigel or extracellular matrices, fibronectin, laminin, and type IV collagen, as well as cell invasion was dose dependent in both cell lines. When ED, EL and TAM were combined at 1 microM, a greater inhibitory effect on cell adhesion and invasion was observed than with either compound alone. ED and EL at doses of 0.1-10 microM reduced cell migration, but TAM had no effect at 0.1 and 1 microM, and exhibited a stimulatory effect at 10 microM. It is concluded that lignans and TAM, alone or in combination, can inhibit the steps involved in the metastasis cascade. Although more investigations are required, the study also suggests that the intake of the lignan-rich flaxseed may not antagonize the effect of TAM in ER- breast cancer cells.

4-Butyrolactone↗
PubMed2003

Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells.

Oestrogen receptor (ER) levels are usually maintained on acquisition of tamoxifen resistance in the clinic, however, tumour re-growth is associated with increased expression of epidermal growth factor receptor (EGFR) and activation of the mitogen activated protein kinase (MAPK) pathway. In the present study we have used the ER down-regulator fulvestrant ('Faslodex') to investigate the influence of the ER on growth of a tamoxifen-resistant (TAM-R) human breast cancer cell line. Expression levels of ER mRNA and protein were equivalent in parental wild-type MCF-7 (WT) and TAM-R cells. Fulvestrant eliminated ER protein expression and inhibited proliferation in both cell lines. The growth inhibitory effects of fulvestrant were associated with a decrease in basal EGFR, c-erbB2 and ERK1/2 activity in TAM-R but not WT cells. ER functionality as determined by oestrogen response element (ERE)-luciferase reporter activity and expression of PgR, pS2 and transforming growth factor alpha (TGFalpha) was significantly reduced in TAM-R compared to WT cells and was further decreased by fulvestrant treatment in both cell lines. Epidermal growth factor (EGF) and TGFalpha significantly increased EGFR/MAPK pathway activity in both cell lines. Ligand-induced EGFR/MAPK activation promoted TAM-R cell growth in both the absence and presence of fulvestrant, whereas no proliferative activity was observed under the same conditions in WT cells. These results suggest that the ER modulates EGFR/MAPK signalling efficiency in TAM-R cells possibly through the regulation of TGFalpha availability. This effect may be overcome by the action of exogenous EGFR ligands, which strengthen EGFR/MAPK signalling activity to generate endocrine-insensitive cell growth.

Antineoplastic Agents, Hormonal↗
PubMed1994

Tamoxifen delays the development of resistance to cisplatin in human melanoma and ovarian cancer cell lines.

The development of resistance to cisplatin (DDP) occurs rapidly both in vitro and in vivo, and constitutes a major obstacle to effective therapy. We have previously demonstrated that there is a highly synergistic interaction between tamoxifen (TAM) and DDP against cell lines representative of three different human cancers: melanoma, ovarian carcinoma and small-cell lung cancer. The purpose of these studies was to determine if TAM interferes with the development of resistance to DDP. T-289 melanoma cells and 2008 ovarian cancer cells were cultured with increasing concentrations of DDP +/- TAM in an attempt to induce resistance to DDP. At various time points the cells were removed from culture and the degree of resistance to DDP was quantitated. Concurrent exposure to TAM and DDP decreased both the rate and the absolute magnitude of resistance to DDP in both melanoma and ovarian cancer cell lines. In the T-289 cell line the rate was decreased by a factor of 3.4 +/- 1.4 (P < 0.05), while in the 2008 cell line the rate was decreased by a factor of 2.4 (P < 0.01). TAM decreases the rate as well as the absolute magnitude of in vitro resistance to DDP in both melanoma and ovarian cancer cell lines. These data suggest that the concurrent administration of TAM and DDP may result in a delay in the development of resistance to DDP which may have important clinical implications in the design of DDP-containing regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines.

Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-kappaB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 microM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 microM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein.

Antineoplastic Agents, Hormonal↗
PubMed2004

Tamoxifen and tamoxifen ethyl bromide induce apoptosis in acutely damaged mammary epithelial cells through modulation of AKT activity.

Normal human mammary epithelial cells (HMECs), unlike estrogen receptor-positive (ER+) breast cancers, typically express low nuclear levels of ER (ER-'poor'). We previously demonstrated that 1.0 microM tamoxifen (Tam) induced apoptosis in ER-'poor' HMECs acutely transduced with human papillomavirus-16 E6 (HMEC-E6) through a rapid mitochondrial signaling pathway. Here, we show that plasma membrane-associated E2-binding sites initiate the rapid apoptotic effects of Tam in HMEC-E6 cells through modulation of AKT activity. At equimolar concentrations, Tam and tamoxifen ethyl bromide (QTam), a membrane impermeant analog of Tam, rapidly induced apoptosis in HMEC-E6 cells associated with an even more rapid decrease in phosphorylation of AKT at serine-473. Treatment of HMEC-E6 cells with 1.0 microM QTam resulted in a 50% decrease in mitochondrial transmembrane potential, sequential activation of caspase-9 and -3, and a 90% decrease in AKT Ser-473 phosphorylation. The effects of both Tam and QTam were blocked by expression of constitutively active AKT (myristoylated AKT or AKT-Thr308Asp/Ser473Asp). These data indicate that Tam and QTam induce apoptosis in HMEC-E6 cells through a plasma membrane-activated AKT-signaling pathway that results in (1) decreased AKT phosphorylation at Ser-473, (2) mitochondrial membrane depolarization, and (3) activated caspase-9 and -3.

Apoptosis↗
PubMed2003

Oxidative metabolism of tamoxifen to Z-4-hydroxy-tamoxifen by cytochrome P450 isoforms: an appraisal of in vitro studies.

1. Tamoxifen is used for the prevention and treatment of oestrogen receptor-positive breast cancer. 2. Tamoxifen is metabolized extensively and the formation of Z-4-hydroxy-tamoxifen (Z-4-OH-tam), a potent anti-oestrogen with high affinity for the oestrogen receptor, is believed to be strongly related to the therapeutic benefit achieved following tamoxifen treatment. 3. In vitro studies using human liver microsome preparations have shown considerable interindividual variability in the formation rates of Z-4-OH-tam. 4. Cytochrome P450 (CYP) isoform-specific chemical and monoclonal antibody inhibition studies have demonstrated that CYP2B6, CYP2C9, CYP2D6 and CYP3A4 all mediate the formation of Z-4-OH-tam. 5. Significant associations between the percentage inhibition of Z-4-OH-tam by CYP isoform-specific inhibitors and the rate of metabolism of CYP isoform-specific index reactions and between individual expression of CYP2B6, CYP2C9 and CYP2D6 and Z-4-OH-tam formation rates indicate predominant roles for these isoforms in this pathway. 6. Genotyping of patients with regards to CYP2B6, CYP2C9 and CYP2D6 may play a role in prediction of Z-4-OH-tam formation and, consequently, ultimate therapeutic benefit of tamoxifen treatment.

Animals↗
PubMedDate not supplied

A combination of platinum and tamoxifen in advanced ovarian cancer failing platinum-based chemotherapy: results of a Phase II study.

The treatment of recurrent or progressive ovarian cancer has limited therapeutic potential. The clinical outcome of second-line therapy largely depends on the potential chemo-sensitivity of the tumor expressed during up-front chemotherapy, as well as on the treatment-free interval from the last course of cytotoxic therapy. However, the identification of agents such as tamoxifen (TAM) at nontoxic doses, able to act synergistically with standard chemotherapy, may be useful to overcome resistance. Fifty patients with recurrent or progressive ovarian cancer following platinum (P)-based chemotherapy (28 platinum-resistant and 22 platinum-sensitive) entered a Phase II trial to evaluate the efficacy and toxicity of P re-challenge with the addition of TAM as a chemotherapy response modulator. The choice of the P compound (100 mg/m2 cisplatin or 400 mg/m2 carboplatin, q3 weeks) was made on the basis of the prior total cisplatin dose and the presence of neurotoxicity. TAM was administered at the doses of 80 mg/day for 30 days followed by 40 mg/day for the remaining period of treatment. Toxicity consisted mainly of mild to moderate nausea and vomiting (76%), peripheral neuropathy (43%), nephrotoxicity (4%), anemia (16%), leukopenia (58%) and thrombocytopenia (16%). The overall response to the P-TAM combination was 50% (complete response 30%; partial response 20%) with a median duration of 8.5 months (3-42). Sixty-four percent of the P-sensitive and 39% of the P-resistant patients responded (59% and 33%, respectively, for those bearing measurable disease). The overall median survival was 23 (3-48) and 19 months for the patients with measurable disease (20 months for the P-resistant group). This phase II trial confirmed the activity for a re-challenge employing a P compound and TAM in clinically defined P-resistant ovarian cancer patients. The mild toxicity profile and the relatively low cost of the treatment render further investigations on the P-TAM regimen worthwhile.

Adenocarcinoma, Clear Cell↗
PubMed2000

Results following surgery for recurrent Dupuytren's disease.

This study was designed to assess the subjective and objective results following surgery for recurrent Dupuytren's disease. Nineteen patients (28 fingers) were treated surgically for recurrent contracture and were located for follow-up analysis at a median of 4 years (range, 1-15 years). Seventeen of 28 recurrences involved the small finger and 16 patients had at least one component of Dupuytren's diathesis. For the purpose of analysis the patients were divided into 3 groups: group A (total active range of motion [TAM] < 150 degrees ) consisted of 7 digits treated with limited fasciectomy and interphalangeal arthrodesis, group B (TAM >/= 150 degrees ) consisted of 8 digits treated with dermatofasciectomy and full-thickness skin graft, and group C (TAM >/= 150 degrees ) consisted of 13 digits treated with fasciectomy and local flaps. Total active range of motion reflecting the preoperative, immediately postoperative, and final follow-up values revealed that group C (fasciectomy and local flap) was the only group to maintain a statistically significant TAM improvement from preoperative (205 degrees ) to final follow-up (230 degrees ) analysis. Dermatofasciectomy and full-thickness skin grafting did not prevent recurrent contracture (preoperative TAM = 175 degrees; final follow-up TAM = 150 degrees ). Thirteen patients had abnormal Semmes-Weinstein monofilament testing and 8 had abnormal 2-point discrimination. There were 3 anesthetic digits. Despite these findings, 18 of the 19 patients were unconditionally satisfied with their experience and would undergo the procedure again.

Adolescent↗