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Biomedical subjects

M Gore

Publications and source records attributed to M Gore.

At least 73 records · Page 4Linked to original sources
PubMed1997

A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma.

In a sequential nonrandomized study, 204 consecutive unselected patients aged < 70 years received induction chemotherapy with infusional vincristine and adriamycin with oral methyl prednisolone (VAMP: n = 75) or with additional cyclophosphamide, C-VAMP (n = 129). 38/129 C-VAMP patients also received verapamil during induction as part of a controlled trial with the aim to overcome drug resistance. A median of five courses (range 1-11) of chemotherapy were required before maximal response was attained and this was similar in both groups. An over-all response rate of 71% was noted at the end of induction. The complete remission (CR) rate with C-VAMP was 24%, which was significantly higher (P = 0.04) than the CR rate with VAMP alone (8%). The addition of verapamil did not alter the response rate of C-VAMP. Compliance to VAMP was overall 83% and not affected by the addition of cyclophosphamide. The proportion of patients going on to receive high-dose chemotherapy and an autograft was the same for VAMP and C-VAMP treated patients (71%). The median overall survival (OS) and progression-free survival (PFS) for the whole group were 4.4 years and 2.0 years and no difference in outcome was observed between the different treatment groups. Therefore the addition of weekly cyclophosphamide to VAMP induction therapy has significantly improved the response rates of previously untreated myeloma patients. C-VAMP was not more toxic and did not compromise the chances of receiving an autograft. Verapamil was without influence on any parameters in this study.

Adult↗
PubMed1997

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

Adult↗
PubMed1997

Adaptations of glutathione antioxidant system to endurance training are tissue and muscle fiber specific.

The effect of endurance training on glutathione (GSH) status and antioxidant enzyme system was investigated in skeletal muscle, heart, and liver of female Sprague-Dawley rats pair fed an isocaloric diet. Ten weeks of treadmill training (25 m/min, 10% grade for 2 h/day, 5 days/wk) increased citrate synthase activity in the deep vastus lateralis (DVL) and soleus muscles by 79 and 39%, respectively (P < 0.01), but not in the heart or liver. In DVL, GSH content was increased 33% (P < 0.05) with training, accompanied by a 64% (P < 0.05) increase in glutamate content but no change in cysteine. Trained rats showed a 62 and 27% higher GSH peroxidase (GPX) and superoxide dismutase (SOD) activity, respectively (P < 0.05), in DVL compared with control rats. In contrast, GSH content and glutathione reductase (GR) activity in soleus declined with training (P < 0.05), whereas activities of GPX and SOD remained unchanged. Training did not alter GSH status in the liver or plasma but significantly decreased the GSH-to glutathione disulfide ratio in the heart. In addition, GR activity in the liver and GSH sulfur-transferase activity in the heart and DVL were significantly lower in the trained vs control rats DVL muscle had threefold higher gamma-glutamyl transpeptidase activity compared with other tissues; however no significant alteration was observed in the activity of gamma-glutamyltranspeptidase or gamma-glutamylcysteine synthetase in the liver, heart, or skeletal muscle. These data indicate that endurance training can cause tissue- and muscle fiber-specific adaptation of antioxidant systems and that GSH homeostasis in extrahepatic tissues may be determined by utilization and uptake of GSH via the gamma-glutamyl cycle.

Adaptation, Physiological↗
PubMed1997

Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

PURPOSE: Topotecan and paclitaxel were evaluated in a randomized, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 112) or paclitaxel (175 mg/m2) infused over 3 hours every 21 days (n = 114). Patients had bidimensionally measurable disease and were assessed for efficacy and toxicity. RESULTS: Response rate was 23 of 112 (20.5%) in topotecan-treated patients and 15 of 114 (13.2%) in paclitaxel-treated patients (P = .138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (P = .222) and median times to progression were 23 and 14 weeks, respectively (P = .002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (P = .515). Response rates for topotecan and paclitaxel were 13.3% versus 6.7% (P = .303) in resistant patients (not responded to prior platinum-based therapy or progressed within 6 months of an initial response) and 28.8% versus 20.0% (P = .213) in sensitive patients (progressed > 6 months after response). Neutropenia was significantly more frequent on the topotecan arm 79% versus paclitaxel arm 23% (P < .01). It was short-lasting and noncumulative in both arms. Nonhematologic toxicities were generally mild (grades 1 to 2) for both agents. CONCLUSION: Topotecan has efficacy at least equivalent to paclitaxel manifested by the higher response rate and significantly longer time to progression.

Adult↗
PubMed1996

Effect of acute exercise on glutathione deficient heart.

The role of glutathione (GSH) in myocardial antioxidant defense was investigated in Swiss-Webster mice either performing swim exercise to exhaustion or rested in both the GSH adequate (GSH-A) and GSH deficient (GSH-D) states. GSH deficiency was accomplished by injecting mice with L-buthionine [S,R]sulfoximine (BSO; 2 nmol/kg body wt, i.p.) and providing BSO (20 mM) in drinking water for 12 days. GSH and glutathione disulfide (GSSG) contents in the GSH-D hearts were decreased to 10 and 8%, respectively, of those in the GSH-A mice. This decrease was associated with a significant decline of the total glutathione level in the liver, skeletal muscle and plasma. Myocardial GSH peroxidase and GSH sulfur-transferase activities decreased significantly following GSH deficiency, whereas superoxide dismutase activity was significantly elevated. GSH deficiency did not affect exercise endurance performance. However, exhaustive exercise decreased GSH content in the myocardium of the GSH-A and GSH-D mice by 22 and 44% (p < 0.05), respectively. The GSH:GSSG ratio was not altered significantly following exercise because of a concomitant decrease in GSSG (p < 0.05). gamma-Glutamyltranspeptidase activity was significantly increased after exercise, especially in the GSH-D hearts (72%; p < 0.05). GSH content after exercise correlated negatively with exercise time in both GSH-A and GSH-D mice (p < 0.05). These data indicate that GSH is actively used in the myocardium during prolonged exercise at moderate intensity and that GSH deficiency is tolerated by the heart, possibly compensated for by an increased GSH uptake from the plasma.

Animals↗
PubMed1996

Unknown primary carcinoma: randomised studies are needed to identify optimal treatments and their benefits.

This is a retrospective review of 101 patients with unknown primary carcinoma (UPC) treated between 1989 and 1994, on whom data were collected prospectively. 92 patients received platinum-based chemotherapy and 9 had single agent 5-fluorouracil (5-FU). In the platinum group, an objective response rate of 37.2% was seen, with a median duration of 4.5 months (range 1.9-17.5). There were no responses with 5-FU alone, while median survival was 6.4 months and was not different from the platinum group (P = 0.09). Considerable symptomatic resolution was noted, although the contribution of chemotherapy alone to this is difficult to define. The impact of tumour response on quality of life and survival in UPC requires further elucidation in prospective studies with a "best supportive care' arm. The superiority of platinum-based treatments reported in selected subgroups cannot be applied to the whole spectrum of UPC.

Adenocarcinoma↗
PubMed1996

Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer.

The purpose of this study was to determine the effect of the first rat monoclonal antibody (MAb ICR62) to the epidermal growth factor receptor (EGFR) in a phase I clinical trial in patients with unresectable squamous cell carcinomas. This antibody effectively blocks the binding of EGF, transforming growth factor (TGF)-alpha and HB-EGF to the EGFR, inhibits the growth in vitro of tumour cell lines which overexpress the EGFR and eradicates such tumours when grown as xenografts in athymic mice. Eleven patients with squamous cell carcinoma of the head and neck and nine patients with squamous cell carcinoma of the lung, whose tumours expressed EGFR, were recruited. Groups of three patients were treated with 2.5 mg, 10 mg, 20 mg or 40 mg of ICR62 and a further eight patients received 100 mg. All patients were evaluated for toxicity using WHO criteria. Patients' sera were tested for the clearance of MAb ICR62 and the development of human anti-rat antibodies (HARA). No serious (WHO Grade III-IV) toxicity was observed in patients treated with up to 100 mg of antibody ICR62. Antibody ICR62 could be detected at 4 h and 24 h in the sera of patients treated with 40 mg or 100 mg of ICR62. Only 4/20 patients showed HARA responses (one at 20 mg, one at 40 mg and two at 100 mg doses) and of these only the former two were anti-idiotypic responses. In four patients receiving doses of ICR62 at 40 mg or greater, biopsies were obtained from metastatic lesions 24 h later and examined for the localisation of ICR62 using anti-rat antibody reagent. In these patients we showed the localisation of MAb ICR62 to the membranes of tumour cells; this appeared to be more prominent at the higher dose of 100 mg. On the basis of these data we conclude that MAb ICR62 can be administered safely to patients with squamous cell carcinomas and that it can localise efficiently to metastases even at relatively low doses.

Adult↗
PubMed1996

Platinum agents and secondary myeloid leukaemia: two cases treated only with platinum-based drugs.

With the increasing use of chemotherapy for many different primary malignancies, secondary or therapy-related acute myeloid leukaemias (AML) and myelodysplastic syndromes (MDS) are becoming more common. The risk of developing sAML has been estimated to be between 2% and 10%, depending upon the type, duration and dosage of previous therapy (Michels et al, 1985; Shulman, 1993; Robinson & Mertens, 1993; Ballen & Antin, 1993). It is therefore one of the most serious long-term complications of current cancer treatment and is likely to increase as longer survival rates for the primary tumour are achieved. An increasing range of drugs have been reported to cause sAML, including the alkylating agents, the epipodophyllotoxins and the anthracyclines, both as single agents and in combination (Pedersen-Bjergaard & Philip, 1991; Pedersen-Bjergaard & Rowley, 1994). We report two cases of secondary AML in which platinum compounds were the sole prior chemotherapy.

Acute Disease↗
PubMed1996

'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group.

BACKGROUND: Anti-metabolites such as methotrexate (MTX) and 5-fluorouracil (5-FU) have been used clinically for many years. Although their effects are partly due to thymidylate synthase (TS) inhibition, they also have non-specific, non TS effects on RNA and purine synthesis. Direct and specific TS inhibitors therefore presented an attractive research target. Collaborative research between the Institute of Cancer Research and Zeneca Pharmaceuticals led to the design of specific folate based quinazoline TS inhibitors. ZD1694 ('Tomudex'), the first of these drugs reaching advanced clinical development, is currently completing phase III studies. DESIGN: Eight phase II trials were carried out using 'Tomudex', 3.0 mg/m2, given as a short 15-minute infusion 3-weekly. RESULTS: 'Tomudex' demonstrates activity in a range of tumour types, most notably advanced colorectal and breast cancer (objective response rate 26%) and has acceptable toxicity: the most common WHO grade 3 and 4 adverse events were self-limiting reversible increases in liver transaminases, transient leucopenia, diarrhoea, nausea and vomiting and tiredness or malaise. Mucositis/stomatitis, alopecia and skin toxicity were notable for their low incidence and mild intensity. CONCLUSIONS: 'Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatment of colorectal cancer. Further studies in other tumour types are planned.

Adult↗
PubMed1996

Reverse transcriptase-polymerase chain reaction for expression of tyrosinase to identify malignant melanoma cells in peripheral blood.

BACKGROUND: Circulating tumour cells in the peripheral blood may be important for haematogenous spread of disease. The detection of these cells may therefore be a poor prognostic indicator. Reverse-transcriptase polymerase chain reaction (RT-PCR) of target tumour-specific protein expression has been used as a sensitive and specific method for the detection of these tumour cells. Initial reports by our laboratory and other suggested RT-PCR amplification of the enzyme tyrosinase is a useful method for detection of melanoma cells in peripheral blood [1-3]. PATIENTS AND METHODS: In this report, we have evaluated the application of RT-PCR for tyrosinase mRNA as a detection method for melanoma cells in a series of 24 patients with advanced, metastatic malignant melanoma. A single round RT-PCR method is described. RESULTS: The single round RT-PCR was as sensitive as previously described nested PCR methods, and had the advantage of reduced contamination risks. Blood samples from three out of the twenty-four patients were positive. CONCLUSIONS: The frequency of tumour cell detection in peripheral blood from patients with advanced disease was lower than previously reported. It may be only small numbers of circulating tumour cells are present at any one time in the peripheral blood of patients with malignant melanoma. If this is the case increased sampling will improve detection frequency. Alternatively, dissemination of melanoma through peripheral blood may be a rare event. In our experience, RT-PCR for tyrosinase mRNA as a staging test for melanoma patients must be interpreted cautiously.

Adult↗
PubMed1996

Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study.

PURPOSE: Topotecan is a topoisomerase I inhibitor with preclinical activity against various tumor types. We conducted a large multicenter phase II study with topotecan in ovarian cancer in patients who had failed to respond to one prior cisplatin-based chemotherapeutic regimen. PATIENTS AND METHODS: Topotecan 1.5 mg/m2/d was administered intravenously by 30-minute infusion for 5 days repeated every 3 weeks. As the cisplatin-free interval relates to response in subsequent treatment, patients were stratified in subgroups, ie, cisplatin-refractory, cisplatin-resistant, and cisplatin-sensitive. RESULTS: One-hundred eleven patients entered the study. Nineteen patients were considered to be ineligible; 92 patients were assessable for response. A total of 552 courses were given (median, four per patient; range, one to 17). The major toxicities were leukocytopenia and neutropenia, which were grade 3 to 4 in 54.2% and 69.1% of courses, respectively, but with only 4.3% of these being grade 4 neutropenia plus fever or infectious complications. Prophylactic granulocyte colony-stimulating factor (G-CSF) was given in 20.5% of courses to maintain dose-intensity. Other relatively frequent side effects were alopecia (82%), nausea (36.4%), and vomiting (17.5%). The overall response rate was 16.3%, with one complete response (CR) and 14 partial responses (PRs). In the cisplatin-refractory, cisplatin-resistant, and cisplatin-sensitive strata, the response rates were 5.9%, 17.8%, and 26.7%, respectively. The median duration of time of documented response was 21.7 weeks (range, 4.6 to 41.9). CONCLUSION: Topotecan in a daily-times-five schedule is an effective regimen as second-line treatment in ovarian cancer. Further investigations of topotecan in ovarian cancer, including first-line use and combination with other active agents, are indicated.

Adult↗
PubMed1995

Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer.

BACKGROUND: Because of the relative scarcity of natural paclitaxel (Taxol), which has been recently recognized as a highly cytotoxic agent for use in platinum-refractory ovarian cancer, synthetic and semisynthetic substitutes have been actively pursued. Docetaxel (Taxotere), a new semisynthetic taxoid, has been selected for clinical development because it is twice as potent as paclitaxel in promoting assembly of tubulin and in inhibiting microtubule depolymerization. Docetaxel also shows equal or greater cytotoxicity in relevant preclinical models. PURPOSE: Because docetaxel has produced consistent antitumor responses in ovarian cancer patients in phase I trials, we planned and conducted a phase II clinical trial to evaluate the drug's effectiveness and its toxic effects. METHODS: The present trial, which started in May 1992 and ended in December 1992, involved 97 patients with advanced epithelial ovarian cancer. The target study population had disease relapse or disease progression within 12 months of the last administration of a first-line or second-line platinum-based regimen with at least one bidimensionally measurable target lesion. The patients received docetaxel at a dose of 100 mg/m2 given as a 1-hour infusion every 3 weeks without premedication for minimizing potential hypersensitivity. Docetaxel-induced side effects were graded according to the National Cancer Institute's Common Toxicity Criteria. RESULTS: The overall response rate was 23.6% in 76 assessable patients versus 20% if all 90 eligible patients were included in the comparison (95% confidence interval [CI] = 11%-29%). Among 34 eligible patients whose tumor progressed on the most recent platinum treatment, the response rate was 23.5% (95% CI = 8%-39%). The median progression-free survival for all eligible patients was 3.9 months, and the median overall survival was 8.4 months. Docetaxel-associated toxicity in 90 assessable patients consisted of short-lived neutropenia in 81 (90%) patients, which was complicated by fever and hospitalization in seven (8%); hypersensitivity reactions were seen in 29 (31%) patients, with significant reactions seen in seven (8%); and neurotoxicity in 43 (48%) patients, with grade 3 or above toxicity seen in only three (3%). The treatment also produced skin reactions in 58 (64%) patients, of whom only four (4%) showed the intensity of grade 3. Eleven (12%) patients experienced pleural effusions, which were the effects of the drug considered to be of greatest concern. Peripheral edema and weight gain due to fluid retention were reported in 40 (44%) and 17 (19%) patients, respectively. CONCLUSION: Docetaxel appears to be effective in the treatment of platinum-refractory ovarian cancer patients.

Adult↗
PubMed1995

Increased soluble interleukin-2 receptor concentration in plasma predicts a decreased cellular response to IL-2.

Interleukin 2 (IL-2) immunotherapy has met with limited success in the treatment of renal cell carcinoma (RCC) and malignant melanoma (MM). However, non-responders still account for up to 80% of those patients receiving IL-2. A high concentration of soluble IL-2 receptor (sIL-2R) is commonly found in the blood of such patients. We investigated the possibility that high sIL-2R concentration pretreatment may interfere with the bioavailability of IL-2. The mean concentration of sIL-2R in plasma from patients with MM, RCC and head and neck cancer was 3378 U ml-1, 8778 U ml-1 and 764 U ml-1 respectively, compared with 1315 U ml-1 in plasma from healthy volunteers. Inclusion of plasma from patients with RCC and MM patient plasma in cytotoxic T-lymphocyte leukaemic (CTLL) cell/IL-2 assays inhibited the ability of CTLL cells to respond to IL-2, and an inverse correlation was found between the concentration of sIL-2R and the growth response of CTLL cell to IL-2 (r = -0.86, P = 0.003). Plasma with soluble IL-2R concentrations greater than 3000 U ml-1 produced a reduction in cell growth of more than 50% when included in CTLL IL-2 assays. The addition of increasing concentrations of IL-2 to cultures containing suppressive plasma failed to restore CTLL cell growth response to normal. Failure to saturate sIL-2R by exogenous IL-2 addition therefore suggests that another factor, initially present at a concentration similar to the sIL-2R concentration, is responsible for the observed effect. Determination of the suppressive effect of patient plasma as presented here may allow more effective IL-2 dosing schedules.

Animals↗