Search PubMed⌕ Search

Biomedical subjects

J Carmichael

Publications and source records attributed to J Carmichael.

At least 127 records · Page 7Linked to original sources
PubMed1989

Zoladex: endocrine and therapeutic effects in post-menopausal breast cancer.

The endocrine and therapeutic effects of the LHRH agonist Zoladex have been assessed in 28 post-menopausal women with advanced breast cancer. Fourteen had responded to previous hormone therapy and 14 had no previous hormone therapy. There were two partial responses and two patients with stable disease for more than 6 months in the former group, and one partial response and two with stable disease for more than 6 months in the latter group. Toxicity was minimal. All responses occurred in soft tissue. Six out of seven patients who received tamoxifen after progression of disease on Zoladex showed a response. Peripheral oestradiol levels were measured, and they fell after 1 month from 33 pmol l-1 (+/- 20, s.d.) to 22 pmol l-1 (+/- 11, s.d.) (P less than 0.005). Responders and non-responders showed similar changes in oestradiol. Oestrone levels did not change significantly. These results suggest that Zoladex acts indirectly via changes in peripheral hormones, rather than directly on LHRH receptors on the tumour.

Adult↗
PubMed1989

Glutathione S-transferase isoenzymes in human tumours and tumour derived cell lines.

An increasing body of evidence indicates that glutathione S-transferases play a role in the intrinsic and acquired resistance of tumours to anticancer drugs. In view of the wide use of tumour cell lines to understand the factors which confer either sensitivity or resistance to chemotherapeutic agents we have determined glutathione S-transferase (GST) activity and isozyme composition in nine human cell lines. These data have been compared with the values obtained in solid tumours. In most cases overall GST activity was higher in the tumours than in the cell lines. This was most pronounced for the breast tumour samples relative to MCF7 cell line. The pi class GST subunit was present at similar concentration in the cell lines and the tumours, and in most cases was the most abundant subunit present. The alpha and mu class GST were expressed in most of the cell lines but at much lower concentration than the pi class subunit. Also considerable variability particularly in the expression of the mu subunits was observed. This was also the case for the expression of these subunits in the solid tumour samples. The levels of these GSTs (when expressed) in the solid tumours was invariably higher than that observed in the cell lines. There are therefore several similarities but also some significant differences in GST expression in solid tumours and cell lines. Whether the differences are because expression is lost during the generation of the cell lines or whether it reflects the individuality of human tumours remains to be clearly established.

Cell Line↗
PubMed1989

Arginine vasopressin--a mediator of chemotherapy induced emesis?

Concentrations of plasma arginine vasopressin (AVP) were studied in patients receiving chemotherapy. Of the 18 patients studied, nine experienced nausea and vomiting and the remaining nine were nonvomiters who suffered at worst mild nausea. Plasma AVP in the non-vomiting group remained within the normal range (0.5-1.5 pmol 1(-1] throughout the sampling period. However, patients who vomited showed (with one exception) substantial rises in AVP ranging from 4 to 129-fold. Plasma AVP concentrations were outside the normal range in vomiters and were higher than in non-vomiting patients at 3 h (P less than 0.05) and 5h (P less than 0.01) after chemotherapy. One patient was sampled during consecutive treatment courses, once as a vomiter and once as a non-vomiter; results demonstrated a 16-fold rise in AVP as a vomiter and no rise as a non-vomiter. Significant changes in plasma AVP levels were also observed in patients who suffered moderate or severe nausea compared to those who had mild or no nausea (P less than 0.05). Plasma AVP may prove to be a good objective marker for nausea in future anti-emetic trials.

Adult↗
PubMed1989

Zoladex: therapeutic effects in postmenopausal breast cancer.

The endocrine and therapeutic effects of the luteinising hormone-releasing hormone (LHRH) analogue, Zoladex, have been assessed in 28 postmenopausal women with advanced breast cancer. Fourteen had responded to previous hormone therapy and 14 had received no previous hormone therapy. Zoladex treatment resulted in 2 partial responses and 2 patients with stable disease for more than 6 months in the former group, and 1 partial response and 2 with stable disease for more than 6 months in the latter group. Toxicity was minimal. All responses occurred in soft tissue disease. Peripheral oestradiol levels fell after 1 month of Zoladex from 33 pmol/l (+/- 20 SD) to 22 pmol/l (+/- 11 SD) (p less than 0.005) and both responders and nonresponders showed similar changes in oestradiol. Oestrone levels did not change significantly. Six out of 7 patients who received tamoxifen after progression of disease on Zoladex, showed a response. These results suggest that Zoladex acts indirectly via changes in peripheral hormone levels rather than directly on LHRH receptors on the tumour.

Adult↗
PubMed1988

A phase II study of ifosfamide/mesna with doxorubicin for adult soft tissue sarcoma.

In a phase II study, 16 adult patients with locally advanced or metastatic soft tissue sarcomas were treated with i.v. infusions of ifosfamide/mesna 5 g/m2 plus i.v. doxorubicin 40 mg/m2. Courses were given every 3 weeks up to a maximum of six courses in responding patients. Six patients (37.5%) had either complete (1 patient) or partial responses (5 patients). Confidence limits for this response rate were 15.2%-64.5% (95% confidence level). There was one toxic death in association with encephalopathy, renal and bone marrow failure. Unilateral pneumothoraces occurred in 2 patients with large pulmonary metastases. Recurrent severe ifosfamide/mesna encephalopathy occurred in 2 patients at risk for this complication; patients who develop severe ifosfamide/mesna encephalopathy should not be retreated with this drug. Ifosfamide/mesna with doxorubicin is an active combination to treat adult soft tissue sarcoma but, despite the feasibility of the combination, sequential monotherapy with these drugs might provide similar or better clinical benefit.

Adolescent↗
PubMed1988

Radiation sensitivity and study of glutathione and related enzymes in human colorectal cancer cell lines.

A panel of 13 human colorectal cell lines was studied, with these lines exhibiting a histological profile similar to that observed in clinical practice. In the five lines tested, variable sensitivity to radiation was observed, from the relatively sensitive NCI-H716 to the highly resistant line NCI-H630, with the latter cell line derived from a patient who had previously received radiation treatment. Glutathione levels and glutathione related enzyme activity varied widely between all 13 cell lines, showing no relationship to radiation sensitivity. The variability observed suggests that some colonic tumours may be responsive to radiation, although their identification remains difficult. However, this may prove possible by incorporation of recently developed cell adhesive matrix assays using survival following a 2 Gy radiation dose as a parameter of radiation sensitivity. This panel of human cancer cell lines offers an ideal model for the study of parameters affecting the radiosensitivity and chemosensitivity pattern of colorectal cancer cells.

Cell Line↗
PubMed1988

Results of therapeutic cranial irradiation in small cell lung cancer.

A large proportion of patients with small cell lung cancer develop intracranial metastases which are often severely disabling. The optimal radiotherapeutic program for treating these metastases is unknown. We therefore evaluated objective response rates, response duration, and survival after therapeutic cranial irradiation in 59 patients with proven brain metastases from small cell lung cancer. Objective responses to a variety of doses and schedules were observed in 37 (63%) patients. However, progression of intracranial disease after radiotherapy was common, with 24 responding patients having relapsed in the brain prior to death. The actuarial likelihood of remaining free of progressive brain tumor at 1 year was only 37% in complete and 0% in partial responders. Patients who received radiation doses of more than 40 Gy had longer response durations than those given lower doses, although patient selection could well explain this observation. Brain metastases presenting after initiation of systemic chemotherapy or occurring in conjunction with other sites of extrathoracic disease were associated with a poor prognosis. In patients who present with brain metastases as the sole site of metastatic disease, higher doses of cranial irradiation should be considered, in view of the high intracranial relapse rate associated with currently accepted dose and fractionation schedules.

Adult↗
PubMed1988

Chemosensitivity testing of human lung cancer cell lines using the MTT assay.

Thirty human lung cancer cell lines were tested for chemosensitivity using the semi-automated, non-clonogenic MTT assay. The tumour cell lines came from three major categories of patients: untreated small cell lung cancer (SCLC); SCLC relapsing on chemotherapy; and non-SCLC predominantly from untreated patients. From these data IC50 values were derived for each drug in each cell line. While some inter-experimental variability was observed, the rank order of chemosensitivity of each cell line within this panel was significantly correlated between experiments. These results show that tumour cell lines derived from untreated small cell lung cancer patients were the most chemosensitive for adriamycin, melphalan, vincristine and VP16 compared to the other cell types. In addition, untreated SCLC was more sensitive than non-SCLC to BCNU and cis-platin, while vincristine was the only drug to which treated SCLC was more sensitive compared to the non-SCLC lines. In contrast, no significant differences between the lung cancer types were observed for vinblastine. Thus, this panel of lung cancer cells exhibited a drug sensitivity profile paralleling that observed in clinical practice. These results suggest that this lung cancer cell line panel in combination with a relatively simple but reproducible chemosensitivity assay, such as the MTT assay, has potential for the testing of drug combinations and evaluating new anti-cancer agents in vitro.

Antineoplastic Agents↗
PubMed1988

A phase 1 and pharmacokinetic study of didox: a ribonucleotide reductase inhibitor.

A phase 1 study of a new ribonucleotide reductase inhibitor, didox, was performed by administration of escalating doses of the drug by slow i.v. injection. Thirty-four patients with unresponsive metastatic carcinoma received the drug. There were 13 escalations of dosage, from a starting dose of 192 mg m-2 to 10 g m-2. Dose limiting toxicity was encountered at 7.5 g m-2 where disturbances of hepatic and renal function were observed, in addition to severe gastrointestinal toxicity. Pharmacokinetic studies showed that a peak level of didox was achieved within 5 minutes of injection. At 1,728 mg m-2 the data best fitted a 2 compartment open model, with a mean serum alpha t1/2 of 5.2 min, with a beta t1/2 of 41.3 min. Less than 10% of the drug was excreted unchanged in the urine and the majority of this excretion was within 6 h. Didox can therefore be safely given by slow i.v. injection at a dose of 6 g m-2.

Adult↗
PubMed1988

Glutathione and related enzyme activity in human lung cancer cell lines.

Glutathione levels were measured in 30 human lung cancer lines. Lower levels were detected in cell lines derived from small cell lung cancer specimens compared to non-small cell lines (mean 42 vs. 130 nmol mg-1 protein, P = 0.005). However, no difference were detected between cell lines derived from previously untreated patients, compared to those derived from patients who had received chemotherapy. Non-small cell lines were found to have increased activity of 4 detoxification enzymes compared to small cell lines, although these differences did not reach statistical significance: glutathione transferase activity (69 vs. 36 units, P = 0.137), glutathione reductase (139 vs. 82 units, P = 0.05), gamma-glutamyl transpeptidase (9.39 vs. 3.03 units, P = 0.072) and superoxide dismutase (20 vs. 13.6 units, P = 0.137). As the cell lines exhibit a similar chemosensitivity pattern to that observed in clinical practice, these differences in glutathione and detoxification enzyme levels may prove to be important indicators of intrinsic drug resistance often seen in patients with non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1988

Glutathione S-transferase isoenzymes and glutathione peroxidase activity in normal and tumour samples from human lung.

An increasing body of evidence suggests that glutathione-dependent enzymes are an important factor in determining the sensitivity of tumours to cytotoxic drugs. Ten randomized normal and tumour samples from individuals with lung cancer were analysed for glutathione S-transferase isoenzyme (GST) content and glutathione peroxidase (Gpx) activity. The normal tissue samples exhibited a 5.1- and 7.0-fold variation in GST and Gpx activity respectively. High levels of the pi class, acidic Yf, GST subunit were found in all the samples, with little variation between individuals. The concentration of alpha and mu class subunits was 5- to 10-fold lower and were subject to significant individual variability. The mu class subunit identified had a faster mobility on SDS-PAGE than the hepatic GST mu standard and did not appear subject to the genetic polymorphism associated with certain members of this gene family. This suggests the presence of a novel pulmonary protein which may correspond to the rat Yn Yn protein. The normal to tumour ratio for GST activity varied significantly between the samples and tended to follow the relative expression of the mu class subunit, and to a lesser extent the alpha class GST subunit. The pi subunit was present in the normal and tumour cells in very similar concentration. The expression of the mu class GST appeared to follow the differences in GST enzymic activity and although the numbers were small appeared to segregate according to tumour type. Gpx activity was also elevated in certain tumours. Of particular interest were the two adenocarcinomas which had a 20- to 30-fold higher tumour Gpx activity.

Enzyme Induction↗
PubMed1988

Early stage ovarian cancer: a randomized clinical trial comparing whole abdominal radiotherapy, melphalan, and intraperitoneal chromic phosphate: a National Cancer Institute of Canada Clinical Trials Group report.

Two hundred fifty-seven eligible patients with stage I, IIA "high risk" ovarian carcinoma and IIB, IIIO (disease confined to pelvis), were randomized to either total abdominal radiotherapy (arm A) 2,250 rad in 20 fractions (107 patients), melphalan (arm B) 8 mg/m2/d X 4 every 4 weeks X 18 courses (106 patients), or intraperitoneal chromic phosphate (arm C) 10 to 20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy; arm A, 2,250 rad in ten fractions; and arms B and C, 4,500 rad in 20 fractions. Entry to arm C was discontinued early because of toxicity. In a multifactor analysis using proportional hazards models, no significant difference in survival was observed although there was a marginally significant difference in disease-free survival (P = .015) with arm B being superior to arm A. Stage (P less than .0001), grade (P less than .0001), and histology (P less than .008) were predictors of survival in the multifactor analysis. Performance status, age, and residual disease were significant predictors in the single factor analysis but were not predictive when correction was made for the effects of stage, grade, and histology. Five-year survival rates are 62% for arm A, 61% for arm B, and 66% for arm C. Median duration of follow-up is 8 years. Long-term complications of radiotherapy were seen in 19 patients on arm A, 11 on arm B, and 11 on arm C. Four patients who had received melphalan developed either a myelodysplastic syndrome or acute leukemia. Violations in covering the whole abdominal target volume were correlated with survival.

Chromium↗
PubMed1988

Chinese hamster pleiotropic multidrug-resistant cells are not radioresistant.

The inherent cellular radiosensitivity of a Chinese hamster ovary pleiotropic cell line that is multidrug resistant (CHRC5) was compared to that of its parental cell line (AuxB1). Radiation survival curve parameters n and D0 were 4.5 and 1.1 Gy, respectively, for the CHRC5 line and 5.0 and 1.2 Gy, respectively, for the parental line. Thus, the inherent radiosensitivity of the two lines was similar even though key intracellular free radical scavenging and detoxifying systems employing glutathione, glutathione transferase, and catalase produced enzyme levels that were 2.0-, 1.9-, and 1.9-fold higher, respectively, in the drug-resistant cell line. Glutathione depletion by buthionine sulfoximine resulted in the same extent of aerobic radiosensitization in both lines (approximately 10%). Incorporation of iododeoxyuridine into cellular DNA sensitized both cell lines to radiation. These studies indicate that pleiotropic drug resistance does not necessarily confer radiation resistance.

Animals↗
PubMed1987

Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay.

The in vitro chemosensitivity of 11 human colorectal cell lines to seven chemotherapeutic agents was determined using a semiautomated tetrazolium-based colorimetric assay (MTT assay). Four of the cell lines were from primary tumors and seven from metastases. Eight lines were from patients with no prior chemotherapy. From assay results, we predict 5-fluorouracil (5-FU) to be the sole active agent of the seven tested. This is based on two observations: the range of drug concentrations which produced 50% inhibition of cell growth was greatest with 5-FU (388-fold versus 5- to 30-fold with the other six agents); and the area under the curve (AUC) which produced 50% growth inhibition was within a clinically achievable range only for 5-FU. Since the assay AUC of 5-FU at 50% inhibition was in a clinically achievable range for only two of the 11 cell lines, we performed a multivariate analysis to explore parameters which predict 5-FU sensitivity. In the best fitting model, sensitivity was positively correlated with cloning efficiency in media and with cell surface TAG-72 (a tumor-associated glycoprotein found on epithelial tumors of ovary, lung, colon, and breast origin) expression. If validated with an in vivo test such as the nude mouse model, the MTT assay could be very useful in new drug screening for colorectal carcinoma, for examining combination chemotherapy for synergy, for exploring strategies for biochemical modulation, and perhaps in individualizing therapy when cell lines can be established from a patient.

Antineoplastic Agents↗
PubMed1987

Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing.

Drug sensitivity assays were performed using a variation of a colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)] assay on V79, CHO-AuxB1, CHRC5, NCI-H460, and NCI-H249 cell lines following optimization of experimental conditions for each cell line. Results from this assay were compared with data assimilated simultaneously by clonogenic assay and by dye exclusion assay. Good correlation was observed using the CHO-AuxB1 cell line and the pleiotropic drug-resistant mutant CHRC5, with similar degrees of relative resistance observed with both the MTT and clonogenic assays. Good correlation was observed between the clonogenic and MTT assays for 1-h drug exposures, although the MTT assay was more sensitive to vinblastine. In general, the clonogenic assay was more sensitive when continuous drug exposures were utilized, although this was primarily related to the increased drug exposure time. While the use of the MTT assay in drug sensitivity testing of primary tumor samples is limited, since contaminating normal cells may also reduce the tetrazolium, the MTT assay can be semiautomated, and therefore it offers a valid, simple method of assessing chemosensitivity in established cell lines.

Animals↗
PubMed1987

Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity.

Radiation survival curves were generated for V79 Chinese hamster and two human lung cancer cell lines (NCI-H460 and NCI-H249) with doubling times of 10, 20, and 85 h, respectively, using a standard clonogenic assay, a dye exclusion assay, and a semiautomated colorimetric assay utilizing a tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide. Comparable results for D0 and extrapolation number (n) were observed for all assays in the lines with doubling times of 10 and 20 h. In these instances the tumor cell lines had undergone seven or more doublings after radiation. For the tumor line (H249) with an 80-h doubling time the D0S were comparable between the assays while the extrapolation number was increased in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide assay, a result probably related to the lower number of doublings (less than 4) after radiation. We then tested the ability of the assays to detect radiation protection and sensitization using known agents. We found that cysteamine treatment resulted in radioprotection (by a factor of 8 at 8 Gy) while 5-bromo-2-deoxyuridine incorporation caused enhancement of radiation sensitivity in all three assays. We conclude that, while optimal conditions for each cell line (cell number plated and doubling time) must be established, using characterized tumor cell lines, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylformazan bromide assay could be automated and thus be of great value in screening large numbers of potential radiosensitizers or protectors.

Animals↗