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Biomedical subjects

R M Fox

Publications and source records attributed to R M Fox.

At least 127 records · Page 7Linked to original sources
PubMed1983

Role of radiation therapy in small cell anaplastic carcinoma of the lung.

The previously established roles of radiotherapy in the management of small cell anaplastic carcinoma of the lung have changed with the development of improved chemotherapy. A group of the International Association for the Study of Lung Cancer has concluded that while there is established evidence that the addition of chemotherapy improves the results of radiation therapy, the value of the addition of loco-regional radiation therapy to chemotherapy is uncertain and more difficult to assess. No advantage in short-term (median) survival has been shown in randomized studies, but current data suggest a possible advantage in long-term control of loco-regional disease. Further results of prospective trials are needed to resolve this question. Prophylactic cranial irradiation reduces the incidence of cerebral metastases but so far has not resulted in improved survival. Pending the results of further randomized studies, its routine use in all patients is not advocated. The palliative role of radiation therapy is valuable in symptomatic treatment. Various current modifications of technique to improve the results of conventional radiation treatments with an altered fractionation schedule and use of sensitizers and large fields are not believed to show major advantages. The clear documentation of treatment details and the definition of the criteria for the assessment of results are important if further comparisons of results are to be made possible. In particular, the need for reporting long-term survival at 2 years in contrast to the more usual median survival time is stressed.

Antineoplastic Agents↗
PubMed1983

Flow cytometric analysis of adenosine analogue lymphocytotoxicity.

The induction of G1-phase arrest in T-lymphoblasts by cytostatic concentrations of 2'-deoxyadenosine (R. M. Fox, R. F. Kefford, E. H. Tripp, and I. W. Taylor, Cancer Res., 41: 5141-5150, 1981) prompted a flow cytometric analysis of the cell cycle effects of three other adenosine analogues with known effects on polyadenylated RNA metabolism in an attempt to further explore the nature of 2'-deoxyadenosine 5'-triphosphate-mediated lymphotoxicity. Cytostatic concentrations of 9-beta-D-arabinofuranosyladenine induced an S-phase block, while 3'-deoxyadenosine (cordycepin) and tubercidin (7-deazaadenosine) induced a cycle-nonspecific block. Furthermore, total cellular RNA content was unaltered by 2'-deoxyadenosine or 9-beta-D-arabinofuranosyladenine, but 3'-deoxyadenosine and tubercidin caused a marked reduction in total cellular RNA at minimally cytostatic concentrations. At concentrations of 0.3 to 20 microM, all of these nucleosides were toxic to nondividing peripheral blood lymphocytes, suggesting that in these cells their mechanism of action does not involve reactions associated with DNA replication. Inhibition of polyadenylated RNA metabolism by triphosphate derivatives of adenosine analogues may account for lymphocytotoxicity in nondividing cells, but the demonstrated diverse effects of these nucleosides on nucleic acid metabolism in dividing cells preclude elucidation of the mechanism of the unique induction of G1-phase arrest by 2'-deoxyadenosine.

Adenine Nucleotides↗
PubMed1982

Single-agent versus combination antiemetic treatments in patients receiving cytotoxic chemotherapy.

We report the results of two clinical trials in which patients receiving either doxorubicin (Adriamycin)/cyclophosphamide or cis-platinum cytotoxic chemotherapy were assigned at random either a single or a combination antiemetic treatment. The aim of each trial was to assess whether combination antiemetic therapy would result in improved efficacy. Sixty patients commencing doxorubicin/cyclophosphamide therapy were divided in two random groups to receive either haloperidol or haloperidol plus amitriptyline, and 80 patients commencing cis-platinum therapy were divided at random to receive either metoclopramide or metoclopramide plus promethazine. No statistically significant differences were apparent between single and combination antiemetic regimens in either of the two treatment groups. Antiemetic agents were generally well-tolerated, but minor side effects were common. The failure of our combination antiemetic regimens to intensify the proven antiemetic efficacy of single agents emphasises the need for re-evaluation of currently used antiemetic agents and their dosage schedules.

Amitriptyline↗
PubMed1982

Four-drug combination chemotherapy for advanced cervical carcinoma.

Thirty-one patients with advanced stage squamous cell carcinoma of the cervix were treated with the four-drug combination fluorouracil, doxorubicin, cyclophosphamide, and vincristine. Four patients achieved complete remission (13%) and 15 partial remission (45%). The only factor of adverse prognostic significance was poor initial patient performance. Median survival for the patients entering complete remission exceeded 54 weeks and was 43 weeks for patients achieving partial remission. Seven patients are still alive at 50 weeks. This represents a notable prolongation of survival compared with those patients who did not achieve remission. Toxicity for the combination was not excessive; myelosuppression and vincristine-induced neuropathy were the most prominent. These results are moderately encouraging and confirm the sensitivity of cervical carcinoma to systemic chemotherapy. Further studies to define the optimal use of chemotherapy in both advanced and earlier stages of disease are warranted.

Adult↗
PubMed1982

Deoxycoformycin-induced response in chronic lymphocytic leukaemia: deoxyadenosine toxicity in non-replicating lymphocytes.

The occurrence of severe immunodeficiency disease in children with inherited adenosine deaminase deficiency, and reports of remission induction in T-cell acute lymphoblastic leukaemia with the adenosine deaminase inhibitor deoxycoformycin, prompted a study of the effects of deoxyadenosine on resting peripheral blood lymphocytes (PBL) and chronic lymphocytic leukaemic (CLL) lymphocytes in short-term culture. In the presence of an inhibitor of adenosine deaminase, micromolar concentrations of dAdo caused elevation of deoxyadenosine-5'-triphosphate (dATP) pools and in vitro lysis of non-dividing PBL and CLL lymphocytes. This death of non-replicating cells indicates a mechanism of deoxyadenosine toxicity independent of DNA replication and ribonucleotide reductase inhibition. Similar changes occurred in vivo in a patient with advanced CLL who responded to treatment with deoxycoformycin, 0.1 mg/kg, days 1-5, with a fall in the WCC from 102.0 x 10(9)/1 to 6.8 x 10(9)/l over 21 d. Therapeutic blockade of deoxyadenosine catabolism deserves further investigation both in the treatment of lymphoproliferative disease and as a method lympholytic immunosuppression.

Adenosine Deaminase Inhibitors↗
PubMed1982

Advanced ovarian cancer: a prospective randomised trial of chlorambucil versus combined cyclophosphamide and cis-diamminedichloroplatinum.

Thirty-seven patients with advanced ovarian cancer were treated in a prospective, randomised trial comparing chlorambucil with a combination of cyclophosphamide and cis-diamminedichloroplatinum (cis DDP). Treatment with the combination was associated with an increased overall response rate (69% versus 23%) (p = 0.04). A response was associated with a longer median survival but no survival advantage was demonstrated for patients who received cyclophosphamide/cis DDP. A larger study is needed to evaluate fully the potential of regimens containing cis DDP in the management of advanced ovarian cancer.

Chlorambucil↗
PubMed1982

A rapid high-performance liquid chromatographic method for quantitation of 5-fluorouracil in plasma after continuous intravenous infusion.

A fast, simple, precise, high-performance liquid chromatographic method for the assay of 5-fluorouracil in plasma from humans receiving continuous intravenous infusion is described. After a single extraction, underivatised 5-fluorouracil is assayed by high-performance liquid chromatography using a variable-wavelength ultraviolet detector. After extraction of 1 ml plasma, 0.3 mumol/l can be assayed. The assay is reproducible and linear up to at least 40 mumol/l. A single determination takes 3 hours and a batch of 40 specimens can be extracted and assayed in 4 working hours if automated equipment is used, enabling injections and calculations to be done overnight.

Chromatography, High Pressure Liquid↗
PubMed1982

Use of aminoglutethimide as second-line endocrine therapy in metastatic breast cancer.

Sixty-five patients with advanced breast cancer, progressive despite prior endocrine therapy in all cases and prior chemotherapy in most cases, were treated with aminoglutethimide, 250 mg four times a day. At present, 52 are evaluable for response assessment, and of these 10 (19%) showed an overall objective response, major sites of response being soft tissue and lung. A further 12 patients (23%) had stable disease during aminoglutethimide therapy, while a total of 9 patients with bone metastases reported marked relief of pain without objective evidence of response. Forty-nine patients had received prior treatment with tamoxifen, and of the 10 tamoxifen responders 4 (40%) responded to subsequent aminoglutethimide, while of the 20 tamoxifen failures only 2 (10%) responded to subsequent aminoglutethimide. Aminoglutethimide was reasonably well tolerated, although 6 patients (0%) discontinued treatment because of intolerable side effects. Six of the 10 responding patients have subsequently relapsed, with a mean duration of response of 17 weeks, but 4 continued to respond at 24, 32, 55, and 111 weeks, respectively. The median survival from the start of aminoglutethimide therapy is in excess of 41 weeks for responders and 11 weeks for nonresponders, while the median survival from first relapse is 48 months for aminoglutethimide responders and 28 months for aminoglutethimide nonresponders. These results confirm that aminoglutethimide can offer a useful alternative form of endocrine therapy for advanced breast cancer, but the response rates obtained in heavily pretreated patients are inferior to those obtained when aminoglutethimide is used earlier in sequential treatment. For optimal results, particularly in terms of quality of life, aminoglutethimide should generally be used prior to chemotherapy.

Adult↗
PubMed1982

Characterization of transformed cells and tumors by proton nuclear magnetic resonance spectroscopy.

Cultured acute lymphoblastic leukemic cells give a well-resolved proton nuclear magnetic resonance spectrum characteristic of isolated plasma membranes. We demonstrate that the signals, in the spectrum of whole cells, arise predominantly from the plasma membrane and that cells transformed by pokeweed mitogen have membranes which are significantly less rigid than are normal human peripheral blood lymphocytes. Normal thymus, malignant thymus, and a leukemic T-cell line have been compared by proton nuclear magnetic resonance spin echo experiments, and the normal thymus was found to differ. Cells transformed by the Epstein-Barr virus can also be characterized and shown to differ from the leukemically transformed cells by spin echo experiments. Since no probe molecule was required to obtain these results, this is the first definitive evidence that the structure and fluidity of the plasma membranes change as a result of transformation of lymphocytes. Proton nuclear magnetic resonance spectroscopy can now be used to compare the effect of different mitogens on T- and B-lymphocytes as well as to monitor the effects of drugs, metals, etc., on the plasma membrane of transformed lymphocytes.

B-Lymphocytes↗
PubMed1982

Purine deoxynucleoside toxicity in nondividing human lymphoid cells.

Cultured leukemic T-lymphoblasts, incubated in the presence of inhibitors of adenosine deaminase, are exquisitely sensitive to growth inhibition by deoxyadenosine. An analogy between this phenomenon and human combined immunodeficiency disease associated with inborn adenosine deaminase deficiency and the use of inhibitors of adenosine deaminase in the management of T-cell acute lymphoblastic leukemia has been noted. These phenomena are believed to reflect accumulation of high intracellular concentrations of deoxyadenosine triphosphate (dATP) following phosphorylation of deoxyadenosine, inhibiting replicating T-cells. In an attempt to extend these observations to noncultured, nonleukemic T-cells, we studied deoxyadenosine metabolism in human thymocytes. Human thymuses were separated into large replicating and small nondividing cell types by centrifugal elutriation. Both thymocyte subpopulations elevated in their dATP pools on incubation with microM concentrations of deoxyadenosine in the presence of erythro-9-[3-(2-hydroxynonyl)]adenosine, an inhibitor of adenosine deaminase. These dATP pool rises were similar in extent to those found in cultured leukemic T-lymphoblasts. However, the finding that small nonreplicating thymocytes elevate their dATP pool was unexpected. This prompted study of unstimulated peripheral blood lymphocytes. These cells (T and non-T) showed a similar elevation of their dATP pool on incubation with deoxyadenosine. Furthermore, these nondividing peripheral blood lymphocytes were killed by microM concentrations of deoxyadenosine in the presence of an inhibitor of adenosine deaminase. The biochemical mechanism of this G0-phase cell death is not known. These findings provide impetus for the investigation of adenosine deaminase inhibitors as lympholytic immunosuppressants or as agents to noncycling malignant lymphoid cells.

Adenosine Deaminase Inhibitors↗
PubMed1982

Phase II study of doxorubicin and mitomycin in non-small cell bronchogenic carcinoma.

Thirty patients with advanced measurable non-small cell bronchogenic carcinoma were treated with a combination of doxorubicin (50 mg/m2 every 3 weeks) and mitomycin (20 mg/m2 every 6 weeks). One complete and three partial responses were observed. This response rate is similar to that reported for either drug used alone.

Carcinoma, Bronchogenic↗
PubMed1982

Ototoxicity in patients receiving cisplatin: importance of dose and method of drug administration.

A total of 146 serial audiograms that were performed for 32 patients who had received cisplatin treatment were analyzed. Fifteen patients developed significant audiometric abnormality after a mean cumulative dose of 203 mg/m2. Ototoxicity was more severe with higher cumulative doses and higher individual doses, and was most marked in those patients receiving bolus injections. Loss of perception of higher frequencies was most common. Symptoms of ototoxicity occurred in 23 patients and included deafness, tinnitus, otalgia, and recruitment. In some patients the symptoms were transient, and not all patients with symptoms developed audiometric abnormalities. Audiometric abnormalities were invariably preceded by one or more symptoms of ototoxicity. Ototoxicity resulted in dose modification or cessation of treatment in only three patients, and in each case the decision to modify the dose was made on the basis of symptoms of ototoxicity rather than on the audiometric findings. We conclude that audiometry has a limited role in the routine management of patients receiving cisplatin treatment.

Cisplatin↗
PubMed1981

Methotrexate treatment of squamous-cell head and neck cancers: dose-response evaluation.

Seventy-two patients with advanced squamous-cell carcinomas of the head and neck were randomised to receive weekly intravenous methotrexate at doses of either 50 mg/m2 (low dose), 500 mg/m2 (medium dose), or 5 g/m2 (high dose). Patients who failed to respond after four treatments at their initial dose were given four further treatments at the next higher dose. There were two complete responses and 21 partial responses to the initial dose--in 10 out of 22 patients given the high dose, seven out of 27 given the medium dose, six out of 23 given the low dose. A further five out of 16 patients responded after crossing over to a higher dose. Toxicity was more severe with the high-dose regimen. Responders survived significantly longer than non-responders (p less than 0.05), but there was no significant difference in durations of survival among the three treatment groups. Analysis of patients who completed the first four treatments indicated an improved response rate and duration of survival for the high-dose group. Because of toxicity associated with high-dose methotrexate this treatment produces no overall greater benefit than low-dose regimens.

Adolescent↗
PubMed1981

Situations creating ethical stress.

When a new therapeutic procedure, be it either a cytotoxic drug, surgical operation or radiotherapeutic treatment, is introduced into cancer treatment, it generally requires a careful trial involving comparison with a standard or traditional therapy. The introduction of a new drug in cancer therapy is generally a complex matter, and involves several stages of testing. Such agents are identified as potential anticancer drugs on the basis of preclinical screening studies which involve animal tumour models, and the study of the efficacy of drugs on animal and human tumour cells in tissue culture.

Antineoplastic Agents↗