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N Thatcher

Publications and source records attributed to N Thatcher.

At least 37 records · Page 2Linked to original sources
PubMed1998

A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer.

A randomized phase II trial was performed to compare the efficacy and toxicity of interleukin 2 (IL-2) with an IL-2 and interferon alpha (IFN-alpha) regimen for the treatment of metastatic renal carcinoma. Sixty patients with recurrent renal cell carcinoma (RCC) who had previously undergone a nephrectomy were randomized to receive three cycles of IL-2 or IL-2 with IFN-alpha2b. Eighteen MU of IL-2 were administered subcutaneously on Mondays-Fridays for 3 weeks out of 4. Those patients randomized to receive the combination received the same regimen of IL-2 with 9 MU of IFN-alpha2b subcutaneously on Mondays, Wednesdays and Fridays for 3 weeks out of 4. Thirty patients were randomized to receive each arm. Twenty-nine were evaluable in each arm. Twenty-two patients received three cycles of IL-2 but only 14 patients received three cycles of IL-2/IFN-alpha because of the greater toxicity of the combination. The principal toxicities included nausea, fatigue and fever. There were no complete responses in either arm and only two patients who were treated with IL-2 attained a partial response. Twelve patients in each arm had stable disease and 15 patients in the IL-2 arm and 16 patients in the IL-2/IFN-alpha arm progressed through treatment. There were no significant differences in survival. Ten patients who received IL-2 are alive with a median follow-up of 266 days, whereas six patients who received IL-2/IFN-alpha are alive after a median of 278 days. The median survival from the time of identification of metastatic disease is 444 days in the IL-2 arm and 381 days in the IL-2/IFN-alpha arm. The IL-2/IFN-alpha combination is more toxic than IL-2 alone and this resulted in a reduced number of cycles of treatment. However, the median survival of the two groups was the same, suggesting that further evaluation of the IL-2/IFN-alpha combination should be confined to large prospective randomized clinical trials.

Adult↗
PubMed1998

O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma.

Resistance of tumour cells to methylating and monochloroethylating agents in vitro and in vivo has been linked to levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In a clinical trial of temozolomide in advanced malignant melanoma, the relationship between pretreatment MGMT levels in biopsies of cutaneous tumours and involved lymph nodes and clinical response to the drug has been studied. Among 50 evaluable patients, there were three complete responses (CR), four partial responses (PR), six with stable disease (SD) and 37 with progressive disease (PD), with an overall response rate of 14%. In 33 patients in whom MGMT level and clinical response could be evaluated, the tumour MGMT levels (fmol mg(-1) protein) were: CR, 158 +/- 119; PR, 607 +/- 481; NC, 171 +/- 101; PD, 185 +/- 42.3. Thus, measurements of pretreatment levels of MGMT in melanoma did not predict for response to temozolomide.

Adult↗
PubMed1998

Chemoprotective gene transfer I: transduction of human haemopoietic progenitors with O6-benzylguanine-resistant O6-alkylguanine-DNA alkyltransferase attenuates the toxic effects of O6-alkylating agents in vitro.

Retroviral transduction was used to introduce cDNAs encoding two mutants of human O6-alkylguanine-DNA alkyltransferase (hAT), one of which (hATPA) is 16 times more resistant to O6-benzylguanine (O6-beG), and the other (hATPA/GA) which is almost totally refractory to inactivation relative to the wild-type protein, into K562 human erythroleukaemic cells. A colony-forming assay was used to demonstrate significant protection (P < 0.001) against mitozolomide or temozolomide toxicity in K562 clones expressing either hAT mutant, as determined from an in vitro assay of activity. However, protection against these agents was reduced in hATPA expressing cells in the presence of 1 microM O6-beG and was lost in the presence of 20 microM O6-beG while cells expressing hATPA/GA retained protection even in the presence of 20 microM O6-beG (P < 0.001). Using primary human cord blood-derived CD34+ haemopoietic cells in which PCR analysis indicated that up to 70% of progenitors were transduced with retroviral constructs harbouring hATPA/GA, we observed significant protection of the granulocyte-macrophage colony-forming cells against mitozolomide (P < 0.05) and temozolomide (P < 0.001) induced toxicity in the presence of O6-beG. These findings indicate that retrovirus-mediated expression of hATPA/GA in primitive primary human haemopoietic cells is possible and does provide O6-beG-resistant protection for these cells. Using this strategy in patients may simultaneously permit attenuated myelosuppression and increased sensitivity of tumour cells to the effects of O6-alkylating agent chemotherapy. These data, taken together with the study reported by Chinnasamy et al in the accompanying article in this issue showing reduced toxicity and clastogenicity in murine haemopoietic progenitors, make a compelling case to test this strategy clinically.

Antigens, CD34↗
PubMed1998

Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase.

Murine bone marrow cells were transduced ex vivo with a retrovirus encoding an O6-benzylguanine (O6-beG) insensitive, double mutant form of the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (hATPA/GA). In animals reconstituted with the transduced bone marrow, about 50% of cells in the multipotent spleen colony-forming cells (CFU-S) and lineage restricted granulocyte-macrophage (GM-CFC) haemopoietic progenitor populations were found to be carrying the transgene and this correlated with the frequency of bone marrow cells and spleen colonies which stained positive for hATPA/GA by immunocyto-chemistry. Expression of hATPA/GA was associated with significant in vivo protection of both CFU-S (P = 0.001) and GM-CFC (P < 0.024) against the toxicity of the antitumour methylating agent, temozolomide, given in combination with O6-beG. Expression of hATPA/GA also led to a reduction in the frequency of combined O6-beG/temozolomide-induced micronuclei seen in polychromatic erythrocytes (P < 0.003). This study is the first to demonstrate in vivo protection of multipotent haemopoietic progenitors against the toxic and clastogenic effects of an O6-alkylating agent in the presence of O6-beG. It also represents the first report of reduced clastogenesis as a consequence of expression of an O6-beG-resistant ATase. In the accompanying article we report hATPA/GA-mediated resistance of human CD34+ haemopoietic progenitors to combined O6-beG/O6-alkylating agent toxicity. Together these two reports suggest that a gene therapy strategy whereby protection of normal haemopoietic tissue may be combined with O6-beG-mediated tumour sensitisation may be efficacious in achieving an increase in therapeutic index.

Animals↗
PubMed1998

Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients.

PURPOSE: To assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the toxicity of chemotherapy and alters delivered dose-intensity. To assess the feasibility of dose-intensification of chemotherapy in small-cell lung cancer (SCLC) and determine whether it has an impact on outcome. MATERIALS AND METHODS: Patients with good- or intermediate-prognosis SCLC entered a prospective multicenter study that involved a 2 x 2 factorial design with randomization to six cycles of chemotherapy with ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 intravenously (I.V.) on days 1 and 2 and 240 mg/m2 orally on day 3, and vincristine 0.5 mg/m2 I.V. on day 15 (V-ICE) every 3 weeks (intensified arm) or every 4 weeks (standard arm). A second double-blind randomization to subcutaneous GM-CSF (250 microg/m2/d) or placebo for 14 days between chemotherapy cycles was made. RESULTS: Three hundred patients were entered. Myelosuppression was the main toxicity, with no significant difference in the incidence or grade between treatment groups. The incidence of febrile neutropenia and bacteriologically confirmed sepsis was unaffected by chemotherapy schedule or use of GM-CSF. Twenty-six percent greater dose-intensity was delivered in the intensified arm, with a trend for greater dose-intensity for those who received GM-CSF. Eighty-three percent of patients achieved a response (51% complete response [CR] rate), with no significant difference in response rates between treatment groups. Survival was significantly increased in the intensified compared with the standard arm (P = .0014); median survival rates were 443 versus 351 days and 2-year survival rates were 33% versus 18%, respectively. CONCLUSION: GM-CSF does not reduce the incidence of complications from myelosuppression of aggressive chemotherapy. Dose intensification of V-ICE to a 3-week schedule in SCLC is not associated with increased toxicity, but appears to improve survival significantly. Future studies should aim to deliver chemotherapy in maximal-tolerated dose-intensities.

Adult↗
PubMed1998

Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.

PURPOSE: In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS: Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively. RESULTS: Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION: Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.

Adult↗
PubMed1998

Dose intensity in small cell lung cancer.

Evidence from preclinical models and from clinical trials describing the importance of dose intensity in securing a better treatment outcome is reviewed. Recent randomized trials have shown statistically significant survival benefits with higher-dose, accelerated chemotherapy regimens with and without granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. The novel use of peripheral blood progenitor cells contained in whole blood autotransfusions, which allow a marked increase in dose intensity of an ifosfamide/carboplatin/etoposide regimen, could provide a much easier method of delivering dose-intensive chemotherapy than previously available.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Management of chemotherapy-induced anemia in solid tumors.

Patients with cancer have inappropriately low levels of endogenous erythropoietin for the degree of anemia and further suppression of erythropoiesis results from chemotherapy. Patients with lung cancer, in particular, require a high frequency of transfusions, as they are unable to tolerate the symptoms of anemia due to their underlying pulmonary disease and, often, their age. Data from phase I and II trials indicated that epoetin alfa could increase hemoglobin concentration and reduce transfusion requirements. The beneficial response was dose dependent. These findings were confirmed in a series of three double-blind, placebo-controlled, multicenter phase III trials. Clinical trial evidence indicates that 150 IU/kg epoetin alfa three times weekly effectively treats anemia and decreases transfusion requirements in most cancer patients after the first month of chemotherapy. Furthermore, epoetin alfa will reduce the degree of anemia and markedly reduce the need for transfusions, thereby preventing anemia in patients undergoing multiple cycles of platinum-based combination chemotherapy. Epoetin alfa is well tolerated and shows marked activity in preventing anemia and reducing blood transfusion requirements in patients undergoing cyclic chemotherapy.

Anemia↗
PubMed1997

Expression of the glial glutamate transporter EAAT2 in the human CNS: an immunohistochemical study.

Glutamate transporters play an essential role in terminating the excitatory glutamatergic signal at post-synaptic receptors and in protecting neurones from excitotoxic effects, as well as replenishing the neurotransmitter supply at glutamatergic synapses. The distribution and density of glutamate transporters may be important determinants of vulnerability to glutamate-mediated injury. There is emerging evidence that glutamate transporter dysfunction may be present in motor neurone disease (MND). In this study, a monoclonal antibody, suitable for immunohistochemistry (IHC) in human post-mortem tissue, was produced to the human astrocytic glutamate transporter EAAT2 (excitatory amino acid transporter 2). Western blotting of homogenates of human cortical tissue with the EAAT2 antibody produced a discrete band at 66 kDa. Detailed IHC analysis of the expression of the EAAT2 protein in the human CNS was undertaken. EAAT2 was exclusively localised to astrocytes, with preferential expression in the caudate nucleus, nucleus basalis of Meynert, spinal ventral horn, cerebral cortex and hippocampus, but with lower levels of expression throughout many other CNS regions. Motor neurone groups vulnerable to neurodegeneration in MND appeared distinctive in being surrounded by extensive, coarse, strongly immunoreactive perisomatic glial profiles. Motor neurone groups which tend to be spared in MND, such as those present in the oculomotor nucleus, showed a lower expression of EAAT2, with fewer perisomatic profiles. The EAAT2 antibody will provide a useful tool for increasing our understanding of the role of EAAT2 in excitatory neurotransmission in health and disease states.

ATP-Binding Cassette Transporters↗
PubMed1997

G1 control gene status is frequently altered in resectable non-small cell lung cancer.

Progression through the mammalian cell cycle is controlled by a series of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. Cyclin D1, cdk4 and the tumour suppressors p16 and retinoblastoma protein (pRb) are thought to comprise a linked system governing cell passage through the G1 phase of the cell cycle. Extending an earlier study on cyclin D1 expression, a series of resectable non-small cell lung carcinomas (NSCLCs) was examined for defects in other elements of this control system. Forty-six of fifty-one NSCLC specimens exhibited at least one alteration of these cell-cycle regulators. Immunohistochemical analysis revealed that 33% and 47% of the tumours failed to express pRb and p16, respectively. Failure to detect pRb did not correlate with loss of heterozygosity at the RB1 locus. Eleven of 12 tumours showing positive (normal) pRb staining over-expressed nuclear localised cyclin D1, including 8 with amplification of the cyclin D1 gene (CCNDI). However, in a number of lesions (n = 5) where cyclin D1 was over-expressed but localised to the cytoplasm, pRb expression was undetectable. Sequencing of exons 1 and 2 of the p16 gene (CDKN2) revealed 3/51 tumours with somatic mutations (in addition to 1 case with a germ-line alteration). All of these lesions were positive for p16 protein. No clear homozygous deletions of CDKN2 were observed by multiplex PCR. As assessed by immunostaining using a p16 monoclonal antibody, there was an inverse correlation of pRb and p16 down-regulation. Whilst patients with tumours over-expressing cyclin D1 had a significantly lower incidence of local relapse, the group whose tumours failed to express pRb had a significantly greater risk of local relapse and tended to have shortened event-free survival. Our data show that alteration of at least one cell cycle-regulator gene occurs in the majority of resectable NSCLCs.

Aged↗
PubMed1997

Improving quality of life in patients with non-small cell lung cancer: research experience with gemcitabine.

Alongside objective response rate, quality of life of patients is important in the treatment of cancer, particularly in the palliative setting. Quality of life is difficult to define precisely and is correspondingly difficult to assess. However, a number of methods have been devised and self-report questionnaires are now widely used. Patients with metastatic non-small cell lung cancer (NSCLC) have a poor prognosis with few patients surviving longer than 8 or 9 months. Curative treatment is often not possible and few patients receive active treatment. Although some patients will accept toxic treatments in return for increased survival, it is generally hoped that any treatment, curative or palliative, will not adversely affect patients' quality of life. In three studies in which gemcitabine was used as a single agent in metastatic NSCLC, objective response rates of 20% were obtained. Gemcitabine was well tolerated. Symptoms improved in the studies where disease-related symptoms were assessed. The degree of improvement compared well with historical data on the relief offered by standard radiotherapy and combination chemotherapy. These findings have led to the initiation of a randomised trial to compare the relief offered by gemcitabine plus best supportive care with best supportive care, using quality of life assessments as a primary endpoint.

Adult↗
PubMed1997

Abnormal expression of CCND1 and RB1 in resection margin epithelia of lung cancer patients.

Tumours develop through the accumulation of genetic alterations associated with a progressive increase of the malignant phenotype. In lung cancer, chronic exposure of bronchial epithelium to carcinogens in cigarette smoke may lead to multiple dysplastic and hyperplastic lesions scattered throughout the tracheobronchial tree. Little is known about the genetic alterations in such lesions. This study was carried out to examine cyclin D1 (CCND1) and retinoblastoma (RB1) gene expression in the bronchial epithelium of patients with lung cancer. Lung tumours and their corresponding tumour-free resection margins from 33 patients who underwent resection of non-small-cell lung cancer (NSCLC) were examined by immunostaining with monoclonal antibodies against cyclin D1 (DCS-6; Novocastra) and pRb (NCL Rb-1; Novocastra). Examination of the resection margins revealed four carcinomas in situ, 19 hyperplasias and ten sections showing apparently normal bronchial epithelium. A control group of patients, without lung tumours and who had never smoked, revealed no or weak cyclin D1 and positive pRb staining within bronchial epithelia. Increased cyclin D1 and diminished pRb expression were found in 76% (n = 25) and 27% (n = 9) of the resection margins respectively, and in 12% (n = 4) both cyclin D1 and pRb expression were altered. In the corresponding tumours, 48% (n = 16) were normal, while altered expression was found for cyclin D1 in 33% (n = 11), pRb in 27% (n = 9) and both in 9% (n = 3) of cases. It appears that altered expression of cyclin D1 and pRb is an early event in NSCLC development in almost half of cases analysed. Further investigations are needed to determine the significance of immunostaining of bronchial specimens in individuals at risk of lung cancer, with the possibility that the observations are of importance in the early diagnosis of NSCLC.

Adult↗
PubMed1997

Phase II trial of raltitrexed ('Tomudex') in advanced small-cell lung cancer.

Raltitrexed, a thymidylate synthase inhibitor, was given to 21 patients with advanced small-cell lung cancer, at a dose of 3 mg m(-2) as a 15-min intravenous infusion at 21-day intervals. All of the patients had extensive disease and 17 had received prior therapy. Patients with disease refractory to primary chemotherapy were excluded. Forty-one treatment cycles were given (median two, range one to four). The drug was well tolerated. No objective tumour response was documented. The patients had chemoresistant disease, as shown by a response in only one of ten patients who went on to receive alternative cytotoxic regimens. We conclude that raltitrexed given in this schedule is inactive as second line therapy for small-cell lung cancer.

Adult↗
PubMed1997

Gemcitabine: symptomatic benefit in advanced non-small cell lung cancer.

Recent studies have indicated that chemotherapy not only provides some survival benefit, but also reduces tumor-related symptoms and improves the performance status of patients receiving chemotherapy. Data from single-agent gemcitabine studies demonstrate improvements in a range of tumor symptoms, including cough, hemoptysis, pain, dyspnea, and anorexia, as well as increases in performance status. Indeed, more patients benefit from gemcitabine chemotherapy than suggested by the objective response rate. Surveys also have shown that patients are much more likely to accept chemotherapy for what is perceived by health care professionals as potentially small benefits. Gemcitabine has a role in the palliative treatment of patients with advanced non-small cell lung cancer.

Antimetabolites, Antineoplastic↗
PubMed1997

Single-agent paclitaxel in advanced non-small cell lung cancer: single-center phase II study using a 3-hour administration schedule.

The efficacy and safety of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered as a 3-hour infusion was investigated in a phase II study involving 21 patients with stage III/IV non-small cell lung cancer. The study included two quality of life assessments (the Hospital Anxiety and Depression Scale and the Rotterdam Symptom Checklist) to test their suitability for use in a future randomized phase III trial of paclitaxel and best supportive care versus best supportive care alone. Four (19%) of the 21 patients (95% confidence interval, 8% to 38%) achieved a partial response. The median time to disease progression for all patients entered was 19 weeks. Paclitaxel was well tolerated, with dose reduction required in only one patient because of arthralgia/myalgia. No dose reductions, delays, or discontinuations were required for hematologic toxicity. Completion and compliance with quality of life questionnaires was high, and these research tools proved to be acceptable for future use in phase III studies with paclitaxel.

Adult↗
PubMed1996

A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer.

A phase I study to determine the maximum tolerated dose and toxicity of gemcitabine when given as a 24 h infusion to patients with inoperable non-small-cell lung cancer (NSCLC). A total of 24 patients with unresectable stage IIIa-IV NSCLC were entered into the study. Gemcitabine was administered as a 24 h infusion on days 0, 7 and 14. Courses of therapy were repeated every 28 days. There were 16 males and 8 females with a median age of 51 years (range 40-73 years). The WHO performance score was 1 (21 patients) or 2 (3 patients). The TNM stage was IIIa (6), IIIb (10) and IV (8). Three patients were entered at each dose level with six at the maximum tolerated dose (MTD). Dose levels were 10, 20, 40, 80, 120, 180 and 210 mg m-2. The MTD was 180 mg m-2 and dose-limiting toxicity was neutropenia and lethargy. Partial response was observed in five (21%) patients (95% CI 7-42%) lasting 10, 14, 18, 47 and 51 + weeks. The maximum tolerated dose of gemcitabine given as a 24 h infusion was 180 mg m-2.

Adult↗
PubMed1996

Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer.

Amplification of the CCDN1 gene encoding cyclin D1 was examined by Southern blotting and multiplex polymerase chain reaction (PCR) and occurred in 8 of 53 patients (15%) with primary resected non-small-cell lung cancer (NSCLC). These tumours and 17 additional tumours with a normal gene copy number showed overexpression of cyclin D1 (25/53, 47%), as assessed by immunostaining using a monoclonal antibody. In 22/25 cases, cyclin D1 was localised in the cytoplasm, but some (7/25) had simultaneous nuclear staining. This result is in marked contrast to that reported in breast, hepatocellular and colorectal carcinoma studies where immunostaining was invariably nuclear. Examination of a restriction fragment length polymorphic (RFLP) site within the 3'untranslated region of the cDNA following reverse transcriptase (RT)-PCR (29/53 informative cases) showed a strong association between cytoplasmic staining and imbalance in allele-specific message levels. Cyclin D1 overexpression was associated with a poorly differentiated histology (P = 0.04), less lymphocytic infiltration of the tumour (P = 0.02) and a reduction in local relapse rate (P = 0.01). The relative risk of local relapse was 9.1 in tumours without cyclin D1 overexpression (P = 0.01, Cox regression analysis). We conclude that genetic alteration of cyclin D1 is a key abnormality in lung carcinogenesis and may have diagnostic and prognostic importance in the treatment of resectable NSCLC.

Aged↗