Aromatase inhibitors: a dose-response effect?
Explore the source record for details and available documents.
Aminoglutethimide↗
Biomedical subjects
I E Smith
Publications and source records attributed to I E Smith.
Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance.
Human breast tumors that are initially responsive to tamoxifen (TAM) eventually relapse during treatment. Estrogen receptor (ER) expression and function are often preserved in these tumors, and clinical evidence suggests that this relapse may be related to TAM's known agonistic properties. ER can interact with the activator protein-1 (AP-1) transcription factor complex through protein-protein interactions that are independent of ER DNA binding and, in certain ER-positive cells, this may allow TAM to exert an agonist response on AP-1-regulated genes. We, therefore, assessed both AP-1 DNA binding and the known AP-1 activating enzyme, c-Jun NH2-terminal kinase (JNK), in a panel of 30 ER-positive primary human breast tumors with acquired TAM resistance, as compared to a matched panel of 27 untreated control ER-positive breast tumors and a separate control set of 14 primary tumors, which included 7 ER-positive tumors that were growth-arrested by 3 months of preoperative TAM. AP-1 DNA binding activity was measured from cryopreserved tumor extracts using a labeled oligonucleotide probe containing a consensus AP-1 response element by electrophoretic mobility shift assay. JNK was first extracted from the tumor lysates by incubation over a Sepharose-bound c-Jun(1-89) fusion protein, and its activity was then measured by chemiluminescent Western blot by detection of the phosphorylated product using a phospho-Jun(Ser-63)-specific primary antibody. The set of control ER-positive breast tumors growth arrested by TAM showed no significant difference from untreated control tumors in their AP-1 DNA binding and JNK activities. In contrast, there was a significant (P < 0.001) increase in mean AP-1 DNA binding activity for the panel of ER-positive TAM-resistant (TAM-R) tumors as compared to its matched control panel of untreated tumors. Mean JNK activity in the TAM-R tumors was also significantly higher than that found in the untreated tumors (P = 0.038). Overall, there was no significant correlation between JNK activity and AP-1 DNA binding; however, regression analysis showed that, for any given level of JNK activity, the TAM-R tumors possessed a 3.5-fold increase in AP-1 DNA binding activity as compared to the untreated tumors. These findings indicate that, when compared to untreated ER-positive primary breast tumors, TAM-R tumors demonstrate significantly increased levels of AP-1 DNA binding and JNK activity, consistent with experimental models suggesting that TAM-stimulated ER-positive tumor growth may be mediated by enhanced AP-1 transcriptional activity. These observations support the need for further evaluation of these markers in breast tumors as predictors of TAM resistance.
Aged↗
Epirubicin, cyclophosphamide, and UFT plus oral calcium folinate in advanced breast cancer.
Use of continuous-infusion 5-fluorouracil (5-FU) for the treatment of metastatic breast cancer has met with some success in recent years. In order to build on this experience, investigators at the Royal Marsden Hospital and Institute of Cancer Research have combined continuous-infusion 5-FU with other agents active in metastatic breast cancer and observed improved outcome. The current trial, described here, evaluates UFT (uracil plus tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel), an orally delivered and tolerable prodrug of 5-FU, combined with epirubicin and cyclophosphamide, in the treatment of advanced breast cancer.
Antineoplastic Agents↗
Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer.
This study examined whether the addition of tamoxifen to the treatment regimen of patients with advanced breast cancer being treated with the aromatase inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction. Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day letrozole was administered alone for 6 weeks and in combination with 20 mg/day tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued on the combination until progression of disease or any other reason for discontinuation. Plasma levels of letrozole were measured at the end of the 6-week periods of treatment with letrozole alone and the combination and once more between 4 and 8 months on combination therapy. No further measurements were done thereafter. Hormone levels were measured at 2-week intervals throughout the core period. Marked suppression of estradiol, estrone, and estrone sulfate occurred with letrozole treatment, and this was not significantly affected by the addition of tamoxifen. However, plasma levels of letrozole were reduced by a mean 37.6% during combination therapy (P<0.0001), and this reduction persisted after 4-8 months of combination therapy. Letrozole is the first drug to be described in which this pharmacokinetic interaction occurs with tamoxifen. The mechanism is likely to be a consequence of an induction of letrozole-metabolizing enzymes by tamoxifen but was not further addressed in this study. It is possible that the antitumor efficacy of letrozole may be affected. Thus, sequential therapy may be preferable with these two drugs. It is not known whether tamoxifen interacts with other members of this class of drugs or with other drugs in combination.
Adult↗
Analysis and sorting of apoptotic cells from fine-needle aspirates of excised human primary breast carcinomas.
Numerous recent studies have indicated the central role of apoptosis as a determinant of the growth abnormalities occurring with malignancy and of the effectiveness of a wide range of therapeutic manoeuvres in cancer treatment. However, there has been a relative paucity of studies measuring apoptosis in human solid tumours, because of the low incidence of apoptotic cells, the difficulty of identifying cells undergoing apoptosis, and the ethical and practical restrictions on obtaining repeat biopsies from patients during therapy. Fine-needle aspirates (FNAs) may be obtained from breast carcinomas as a minimally invasive technique allowing repeat sampling. We describe an approach in which the in situ end labelling (TUNEL) assay is applied to cells in FNAs prior to their analysis by flow cytometry, which allows many thousands of cells to be analysed automatically by objective criteria. Cells that were discriminated as apoptotic on flow cytometric analysis were sorted onto microscope slides and found to show nuclear morphology typical of apoptotic cells. A statistically significant relationship was found between the flow cytometric analysis and the conventional application of TUNEL on histological sections (P = 0.03). Repeat analyses of FNAs from 12 carcinomas showed a median 2.05% apoptotic cells and an overall coefficient of variation of 34.9%. Of the total variability in 12 tumours, 80% was attributed to variation between tumours, 12% between batches, and 8% was random. Thus, this technique should be able to detect the major differences in the percentage of apoptotic cells that occur between different tumours (range 0.3-11.3% by flow cytometry) and between different phases of treatment, and should provide a useful tool for further research on this process in solid tumours.
Adult↗
Measurements of human breast cancer using magnetic resonance spectroscopy: a review of clinical measurements and a report of localized 31P measurements of response to treatment.
A review of the literature has shown that in human breast tumours, large signals from phosphomonoesters (PME) and phosphodiesters (PDE) are evident. In serial measurements in 19 patients with breast cancer, a decrease in PME was significantly associated with a stable or responding disease (p = 0.017), and an increase in PME was associated with disease progression. Extract studies have shown PME to comprise of phosphoethanolamine (PEth) and phosphocholine (PCho), with the PEth to PCho ratio ranging from 1.3 to 12. The PCho content of high grade tumours was found to be higher than low grade tumours. In some animal models, changes in PCho have been shown to correlate with indices of cellular proliferation, and spheroid studies have shown a decrease in PCho content in spheroids with smaller growth fractions. A serial study of 25 patients with advanced primary breast tumours undergoing hormone, chemotherapy or radiotherapy treatments, showed that in this heterogenous group there were significant changes in metabolites that were seen during the first 3 weeks (range 2-4 weeks) of treatment, that correlated with volume change over this period, employed here as a measure of response. Changes in PME (p = 0.003), total phosphate (TP) (p = 0.008) and total nucleoside tri-phosphate (TNTP) (p = 0.02) over 3 (+/-1) weeks were significantly associated with response, as were the levels of PME (p<0.001), PDE (p = 0.01), TP (p = 0.001) and TNTP (p = 0.007) at week 3 (+/-1). PME at week 3 (+/-1) was also significantly associated with the best volume response to treatment (p = 0.03). A reproducibility analysis of results from the observation of normal breast metabolism in four volunteers showed a mean coefficient of variation of 25%, after correcting for changes resulting from the menstrual cycle. Reproducibility studies in four patients with breast cancer showed a mean coefficient of variation of 33%, with the reproducibility being better in patients measured on different days (difference in TP was -6%) compared with those measured on the same day (difference in TP was -29%).
Adult↗
Continuous infusional chemotherapy for early breast cancer: the Royal Marsden Hospital experience.
5-FU is a cycle-specific S-phase-dependent drug with a short half life of 10-20 min. There is therefore a rationale for its use in long-term continuous infusional therapy, with doses of up to 300 mg/m2 per day proving feasible for prolonged periods. The schedule is active in patients with heavily pre-treated breast cancer, with responses in up to 53% (overall 29%). At the Royal Marsden Hospital we have evaluated infusional 5-FU 200 mg/m2 per day for up to 6 months in combination with 3-weekly bolus epirubicin (E) 60 mg/m2 and cisplatin (C) 60 mg/m2 (infusional ECF) as pre-operative/neo-adjuvant treatment in 123 patients with operable breast cancer greater than 3 cm (median 6 cm), initially in a phase II study of 50 patients and subsequently as part of a randomised phase III trial. One hundred and eighteen (96%) have achieved objective tumour responses, with 67 (57%) achieving CR. The 5-year actuarial survival rate is 78% and the local recurrence rate without associated metastatic disease 12%. The pathological complete remission (CR) rate was 16%, with a further 5% having residual DCIS only. Pathological CR but not clinical CR is an independent predictor for disease-fee survival. The Royal Marsden is now conducting two multicentre randomised trials of infusional ECF: (i) versus conventional AC (adriamycin cyclophosphamide) as pre-operative/neo-adjuvant chemotherapy, with 376 patients so far randomised towards a target of 400; and (ii), more recently, a similar adjuvant trial versus conventional FEC (5-FU, epirubicin, cyclophosphamide), with 168 patients so far randomised. These trials will determine whether encouraging phase II activity with continuous infusional chemotherapy translates eventually into real survival benefit for patients with early breast cancer.
Breast Neoplasms↗
Primary chemotherapy in breast cancer.
Primary (neoadjuvant) chemotherapy is a rapidly evolving area in the management of early operable breast cancer. This approach achieves significant responses in around 80% of patients, with a reduction in the need for immediate mastectomy in patients presenting with large primaries, with no evidence of increased local recurrence. So far randomised trials suggest that survival is as good with primary chemotherapy as with post-operative adjuvant chemotherapy. Primary chemotherapy offers the potential short term tumour response as a predictor for longer term survival. More importantly, it allows serial biological measurements of treated breast cancers which, in turn, may aid the selection of appropriate treatment for individual patients and allow the rapid assessment of new therapies.
Antineoplastic Agents↗
Long-term survival after hepatic resection for metastatic breast cancer: a case report.
Explore the source record for details and available documents.
Breast Neoplasms↗
Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy.
Experimental laboratory data suggest that tumour growth is a balance between apoptosis and proliferation and that suppression of drug-induced apoptosis by oncogenes such as bcl-2 may be an important cause of intrinsic chemoresistance. The aims of this study were to assess the in vivo relationship of apoptosis to proliferation and Bcl-2 protein in human breast tumours both prior to chemotherapy and in the residual resistant cell population at the completion of treatment. We examined apoptotic index (AI), Ki67 and Bcl-2 protein expression in the tissue of 40 patients with operable breast cancer immediately before ECF preoperative chemotherapy, and in 20 of these patients with residual tumour, at the completion of treatment. There was a significant positive association between AI and Ki67 both before and after chemotherapy, and in their percentage change with treatment. In the residual specimens AI and Ki67 were significantly reduced compared with pre-treatment biopsies, while Bcl-2 expression showed a significant increase. No differences were seen in the pre-treatment levels of any of the variables measured between patients obtaining pathological complete response and those who did not, although numbers were small. These data suggest that apoptosis and proliferation are closely related in vivo. It is possible that the phenotype of reduced apoptosis and proliferation, and increased Bcl-2 may be associated with breast cancer cells resistant to cytotoxic chemotherapy, although this can only be proven by assessing larger numbers of patients in relation to pathological response.
Adult↗
Fadrozole and letrozole in advanced breast cancer: clinical and biochemical effects.
Explore the source record for details and available documents.
Antineoplastic Agents, Hormonal↗
Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma.
PURPOSE: To evaluate the therapeutic impact of a simple combination chemotherapy regimen on symptoms related to malignant mesothelioma. MATERIALS AND METHODS: Between October 1986 and June 1997, 39 patients with advanced inoperable malignant mesothelioma were treated with palliative MVP (mitomycin-C 8 mg/m2 q. six weeks, vinblastine 6 mg/m2 q. three weeks and cisplatin 50 mg/m2 q. three weeks) chemotherapy and assessed for objective response and relief of symptoms. RESULTS: Eight of 39 patients (20%) achieved an objective partial response with a median duration of nine months: only five patients had progression of disease during chemotherapy. Twenty-four of 39 (62%) had an overall improvement in their symptomology with particularly good responses for pain (79%). These benefits were independent of performance status. Resolution of symptoms was achieved in all responding patients within two treatment cycles. There was no statistically significant difference in duration and incidence of symptom response in those patients achieving radiological PR compared with those with no change and more than 60% of patients with radiological no change obtained useful symptom control. The treatment was well tolerated with only four patients developing grade 3 leucopenia and three with grade 3 nausea. CONCLUSIONS: MVP is a well tolerated regimen and its use in malignant mesothelioma provides useful symptomatic benefit. These results should be the basis for further trials of MVP in the management of mesothelioma with symptom control as a principal endpoint.
Aged↗
A pilot study of MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in small-cell lung cancer.
MVP chemotherapy (mitomycin C 8 mg m(-2), courses 1, 2, 4 and 6, vinblastine 6 mg m(-2), cisplatin 50 mg m(-2)) is an active low-toxicity regimen in non-small-cell lung cancer (NSCLC). Based on the single-agent activity of these agents in SCLC, we have conducted a phase II trial of MVP in SCLC. Fifty chemo-naive patients with SCLC were entered in this trial. There were 33 men and 17 women with median age 66 years (range 46-83 years); 18 patients had limited disease (LD) and 32 extensive disease (ED). WHO performance status (PS) was: three patients PS 0, 33 patients PS 1, ten patients PS 2, four patients PS 3. A maximum of six cycles was given in responding patients. On completion of chemotherapy, patients with LD obtaining complete response (CR)/good partial response (PR) received thoracic irradiation and those obtaining CR were offered entry into the ongoing MRC Prophylactic Cranial Irradiation Trial. The overall response was 79% with 17% CR and 62% PR. For LD patients, 38% obtained CR but for ED only one patient achieved CR. Median response duration for LD patients was 8 months and for ED patients 5 months. Median survival was 10 months for LD patients and 6 months for ED patients. There was complete resolution of symptoms in 24%, partial improvement in 68%, no change in 2% and progressive symptoms in 6%. As regards toxicity, 24% developed WHO grade 3/4 neutropenia, 16% grade 3/4 thrombocytopenia and 6% significant hair loss. Two patients died during the first week of treatment with neutropenic infection. Quality of life using the EORTC questionnaire (QLC-C30) with lung cancer module demonstrated significant improvements from baseline levels in emotional and cognitive functioning, global QOL, of pain, dyspnoea and cough. MVP, an effective palliative regimen for NSCLC, is also active against SCLC with low toxicity and merits comparison with more toxic conventional schedules.
Aged↗
Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors.
The intention of this study was to identify the pretreatment characteristics predicting for the survival, objective response and symptom relief in patients with non-resectable, non-small-cell lung cancer (NSCLC) managed in the Lung Unit at the Royal Marsden Hospital. This analysis included 290 patients with advanced NSCLC generally treated with a cisplatin-based chemotherapy regimen in one of a series of trials. Thirty-seven pretreatment variables, response and survival data were collected prospectively and analysed using univariate and multivariate methods. By multivariate analysis performance status, disease extent and pattern of metastases along with certain biochemical features were influential independent variables for survival, objective and symptom response. Older age was positively associated with objective response (P = 0.04). When the independent factors for symptom response were used to group patients into prognostic categories, 30-48% of patients with an adverse set of factors had symptom relief. Similarly using the relative risk of death to subgroup the patient population, 54% of patients at high risk of death (greater than 8.0), with a median survival of 2.5 months, had symptom relief. The data are consistent with other studies in identifying the pretreatment factors predicting for survival and objective response. Additionally, older age is positively associated with objective response and the majority of patients with the worst prognosis have symptom relief from treatment with chemotherapy.
Adult↗
Phase II trial of topotecan administered as a 21-day continuous infusion in previously untreated patients with stage IIIB and IV non-small-cell lung cancer.
Topotecan (9-dimethylaminoethyl-10-hydroxycamptothecin) is a topoisomerase I inhibitor. Twenty-six patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) who had received no prior chemotherapy were treated in a multicenter study with topotecan 0.6 mg/m2/day for 21 days by continuous intravenous infusion every 28 days; this starting dose was decreased to 0.5 mg/m2/day in the last 23 patients because of myelosuppression. There was one partial response, for a response rate of 4% (95% confidence interval, 0.1%-19.6%). Median survival was 9 months. One-year survival was 39%. Of the 58 lung cancer symptoms at baseline, 40% were resolved by the end of best response (all in the partial response patient, 62% in stable disease patients, 26% in progressive disease patients). Catheter-related infections complicated 19% of courses. Red-cell transfusions were given in 50% of courses. Toxicity included grade 4 neutropenia (4%), grade 3-4 anemia (19%), grade 4 thrombocytopenia (8%), and catheter-related infections (19% courses). Although the major objective response rate was only 4%, patients treated with topotecan given as a 21-day continuous intravenous infusion experienced a decrease in cancer-related symptoms and a 1-year survival of 39%.
Adult↗
Comparison of in situ methods to assess DNA cleavage in apoptotic cells in patients with breast cancer.
BACKGROUND: Apoptosis has a role in many cellular processes including development, normal tissue homeostasis, and malignancy. This aspect of research is relatively new with distinct methods of analysing disparate biochemical and genetic events to measure apoptotic cells. The use of biotinylated nucleotides to identify DNA strand breaks is a commonly reported method of estimating cells numbers undergoing apoptosis; however, investigators report inconsistent results for a variety of reasons. AIMS AND METHOD: To compare two in situ techniques of measuring apoptosis: in situ nick translation (ISNT) and TdT mediated dUTP-biotin nick end labelling (TUNEL); and to assess DNA cleavage in 20 paired paraffin wax embedded breast cancer tissues from patients; one group who had received no prior treatment and one group who had received chemohormonal treatment. RESULTS AND CONCLUSIONS: Apoptotic scores obtained from paraffin wax embedded human breast cancer after using ISNT and TUNEL methods were not significantly different (p = 0.11). A strong correlation between scores obtained from the two techniques was found (r = 0.758, p < 0.0001). Optimisation of both techniques is crucial to ensure maximal assay performance in breast cancer tissue.
Antineoplastic Combined Chemotherapy Protocols↗
Mask intermittent positive pressure ventilation in chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease.
Noninvasive ventilation in chronic obstructive pulmonary disease (COPD) has been shown to improve arterial blood gases but its long-term role has not been established. We retrospectively studied 26 consecutive patients with hypercapnic ventilatory failure due to COPD in whom oxygen therapy caused worsening hypercapnia (defined as a rise in the daytime arterial carbon dioxide tension (Pa,CO2) to >8.0 kPa or nocturnal transcutaneous carbon dioxide tension (Ptc,CO2) to >9 kPa). All were treated with mask ventilation (15 with nasal and 11 face masks) at night and during daytime naps. Additional oxygen therapy was required in 15 patients. The mean annualized death rate was 10.8% with a 1 and 3 yr survival of 92 and 68%, respectively. After 1 yr the median daytime Pa,CO2 had fallen by 1.35 kPa and the arterial oxygen tension (Pa,O2) had risen by 2.4 kPa. In subjects not using additional oxygen the median overnight Sa,O2 rose by 12% and the Ptc,CO2 fell by 2.8 kPa after 1 yr. The haematocrit was significantly less than pretreatment at 6 months and 1 yr. Quality of life in the domain of role limitation by physical health (measured using the SF-36 questionnaire) improved significantly at 6 months. Survival in this selected group with clinically stable airflow obstruction unable to tolerate oxygen therapy and treated with noninvasive mask ventilation is better than historical controls and is comparable to those able to tolerate oxygen therapy. Poor survival was associated with a low forced expiratory volume in one second, a low body mass index and a high nocturnal transcutaneous carbon dioxide tension. No difference in survival was found between those treated with mask intermittent positive pressure ventilation alone or with mask intermittent positive pressure and supplementary oxygen therapy.
Adult↗
Treatment of ventilatory failure in the Prader-Willi syndrome.
Hypercapnic respiratory failure is a common cause of death in the Prader-Willi syndrome. Its relationship to sleep-disordered breathing has not been established and there are no reports of its successful treatment. We have retrospectively reviewed the records of four patients with the syndrome, who developed ventilatory failure. Daytime arterial blood gas tensions and overnight oximetry traces before and during treatment were compared. Each patient had severe sleep-disordered breathing in association with daytime ventilatory failure. The median overnight mean arterial oxygen saturation (Sa,O2) was 82% and the median minimum was only 41.5%. Initial treatment was with nasal intermittent positive pressure ventilation, and in each case the daytime arterial blood gas tensions were normalized. The patients were maintained on nasal continuous positive airway pressure at night after discharge. Compliance has been good, and at last follow-up (after a median of 4.8 yrs) the daytime arterial gas tensions remained normal, while the median overnight mean arterial oxygen saturation was 95.5% and the median minimum was 84.5%. This study of patients with the Prader-Willi syndrome shows that daytime ventilatory failure is associated with sleep-disordered breathing. It can be reversed with nocturnal noninvasive ventilation and maintenance treatment with continuous positive airway pressure is well tolerated, with no deterioration in respiratory parameters.
Administration, Intranasal↗