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Biomedical subjects

M Ranson

Publications and source records attributed to M Ranson.

72 records · Page 4Linked to original sources
PubMed1993

A randomised dose intensity study in ovarian carcinoma comparing chemotherapy given at four week intervals for six cycles with half dose chemotherapy given for twelve cycles.

BACKGROUND: The importance of dose intensity has not been clearly defined in ovarian cancer and we present a prospectively randomised trial of dose intensity in patients with ovarian cancer. PATIENTS AND METHODS: Ninety-nine patients with FIGO stage Ic, II, III and IV epithelial ovarian cancer were randomised to receive cycles of standard dose cyclophosphamide (600 mg/m2) and carboplatin (300 mg/m2) alternating with adriamycin (50 mg/m2) and ifosfamide (5 G/m2) for 6 cycles at monthly intervals (49 patients) or cycles of half dose cyclophosphamide (300 mg/m2) and carboplatin (150 mg/m2) alternating with adriamycin (25 mg/m2) and ifosfamide (2.5 G/m2) for 12 cycles at monthly intervals (50 patients). Patients in each arm were well balanced for major prognostic factors. RESULTS: The combined clinical response rate (complete response and partial response) on the 6 month arm was 76% compared with 48% on the low dose intensity arm (p = 0.009). With a median follow up of 25.7 months the median survival on the low dose intensity arm is 20.9 months. The median survival point on the 6 month arm has not yet been reached. The median progression free interval on the 12 month arm was 19.8 months, the median value has not yet been reached on the standard arm. The amount of residual tumour following initial laparotomy was the only significant independent variable affecting survival (p = 0.0001). The mean received dose intensity of each drug was greater than 80% of the planned dose intensity. More patients had clinical disease progression during treatment on the low dose intensity arm (42%) when compared to the standard dose intensity arm (8%) (p = 0.0003). Fifteen patients on the standard dose arm experienced a total of 18 delays and 5 patients on the low dose arm experienced 17 delays. Nausea, vomiting and diarrhoea were similar for both standard and low dose cycles of chemotherapy with a consequent benefit for patients receiving fewer cycles even though these were of higher dose. CONCLUSIONS: The combination studied was more effective when given at the higher dose intensity and the improved response and survival was not accompanied by a significant increase in toxicity.

Adenocarcinoma↗
PubMed1992

Phase I/II study of intraperitoneal iproplatin in patients with minimal residual disease following platinum-based systemic therapy for epithelial ovarian carcinoma.

13 patients with minimal residual disease following platinum-based systemic therapy for epithelial ovarian cancer were treated with intraperitoneal iproplatin. A total of three cycles were given at monthly intervals. All patients had minimal residual disease (defined as less than 2 cm in diameter) or positive cytology documented at second look laparotomy following systemic chemotherapy. Iproplatin was administered via a temporary dialysis catheter (n = 11) or a semi permanent Tenckhoff peritoneal dialysis catheter (n = 2). The dose of iproplatin ranged from 150 to 450 mg/m2. No responses to therapy were documented. In this trial the major toxic side effects of iproplatin were thrombocytopenia, diarrhoea, nausea and vomiting. The maximum tolerated dose was 300 mg/m2.

Adult↗
PubMed1991

MMAF for advanced gastric cancer.

65 patients with metastatic gastric carcinoma were treated with a combination of methotrexate 1.5 g/m2 with 5-fluorouracil 1.5 g/m2 on day 1 and doxorubicin 30 mg/m2 with mitomycin 4 mg/m2 on day 14. Cycles of chemotherapy were repeated every 4 weeks. The overall response rate was 29% with 6% complete responses and 23% partial responses. Prognostic factors that individually affected response were Karnofsky performance (P less than 0.002), and site of the primary tumour (P less than 0.007). Multivariate analysis showed that only increasing Karnofsky performance (P = 0.01) and disease status (P less than 0.02) (patients with recurrent tumours responding better than patients with postoperative residual disease and those with inoperable disease) were important in predicting response to therapy. The overall median survival was 7 months. All 4 patients with a complete response are alive in remission at 13, 28, 48 and 52 months from the date of starting chemotherapy. Univariate analysis identified increasing Karnofsky performance (P less than 0.0001), response to chemotherapy (P less than 0.02) and higher serum albumin (P less than 0.03) as prognostic indicators for survival. Multivariate analysis, of pretreatment factors and day 14 full blood count showed that only Karnofsky performance (P less than 0.0001) and day 14 platelet count (P less than 0.03) were shown to predict survival, higher platelet values being associated with decreased survival.

Adenocarcinoma↗
PubMed1991

Fludarabine phosphate for the treatment of low grade lymphoid malignancy.

Thirty-four patients with previously treated, advanced, low grade NHL were treated with Fludarabine, a deamination-resistant analogue of adenosine arabinoside, at a dose of 25 mg m-2 intravenously, daily for 5 days (median number of cycles = 3, range 1-10). Complete remission (CR) was achieved in six and partial remission (PR) in a further seven. Overall, responses were seen in 11/23 patients (48%) with follicular lymphoma and in 2/11 (18%) with low grade, diffuse NHL. Fifteen patients with previously treated CLL and one patient with prolymphocytic leukaemia (PLL) were also treated as above (median no. of cycles = 3, range 1-6). A partial response was seen in three of the 11 evaluable patients with CLL and CR was achieved in the patient with PLL. There were four deaths due to infection and 19 further episodes requiring admission to hospital. No other significant toxicity was reported in a total of 164 cycles of Fludarabine. This agent is active in advanced low grade lymphoid malignancy. Further studies are required to assess its role in newly diagnosed patients.

Antineoplastic Agents↗
PubMed1991

Intensive therapy for small-cell lung cancer using carboplatin alternating with cisplatin, ifosfamide, etoposide, mid-cycle vincristine, and radiotherapy.

Forty patients with small-cell lung cancer (31 patients with limited-stage [LS] disease, and nine patients with extensive-stage [ES] disease but of good performance status) have been treated with an intensive therapy composed of carboplatin alternating with cisplatin, ifosfamide, and etoposide with vincristine on day 14 of each carboplatin cycle. A maximum of six cycles were administered at 3 weekly intervals after the cisplatin combination and 4 weekly after the carboplatin combination. Prophylactic cranial irradiation was given with the first cycle of chemotherapy and thoracic irradiation with the third cycle. The median nadir for neutrophils was 0.47 x 10(9)/L and for platelets, 40 x 10(9)/L. Chemotherapy dosages were not reduced in response to myelosuppression, but treatment was delayed to allow blood count recovery. Sixty-eight percent of patients received all six cycles of chemotherapy, and there were four deaths associated with treatment-related neutropenia. Twenty-eight patients (70%) achieved a complete response (CR) when assessed 1 month after the end of treatment, and a further five patients (12.5%) had a partial response (PR). Median duration of CR was 16 months and of PR, 8 months. Cerebral metastases occurred in 20% of all patients and was the apparent sole site of relapse in 11% of the CR patients. The median survival of the total group was 14 months with an actual 2-year survival of 30% and a minimum follow-up of 28 months.

Adult↗
PubMed1990

Five year follow-up and dose delivery analysis of cisplatin, iproplatin or carboplatin in combination with cyclophosphamide in advanced ovarian carcinoma.

Eighty eight patients with FIGO stage IIb/c (postoperative residual) or III/IV epithelial ovarian cancer were randomised to receive cycles of cyclophosphamide (600 mg/m2) with either iproplatin (240 mg/m2), cisplatin (100 mg/m2) or carboplatin (300 mg/m2). A total of six cycles were given at monthly intervals. Patients were well-balanced for major prognostic factors. There was no significant difference in overall response rate (iproplatin arm, 64.3%, cisplatin arm 72.7% and carboplatin arm 66.7%). There were more complete remissions on the carboplatin arm, 45.8% compared with 21.4% on iproplatin and 22.7% on cisplatin but the difference was not statistically significant (p = 0.11). With a median follow up of 50 months the median survival for the iproplatin arm is 18 months, for the cisplatin arm 19 months and for the carboplatin arm 24 months (p = 0.15). Toxicity was greatest with cisplatin and least with carboplatin. Myelotoxicity limited the dose delivery of iproplatin as measured by total dose, dose intensity and dose intensity product. Carboplatin is at least as effective and less toxic than cisplatin when used in conjunction with cyclophosphamide for the treatment of ovarian carcinoma, and this analogue has been selected for dose intensification studies in this tumour at the Christie Hospital.

Adult↗
PubMed1988

Extracellular matrix modulates the function of human melanocytes but not melanoma cells.

Normal human epidermal melanocytes are attached to a basement membrane, a specialized form of extracellular matrix (ECM), located between the epithelium and underlying dermal tissues. To determine whether ECM influences pigmented cell behavior in vitro, human epidermal melanocytes and melanoma cells were cultured on uncoated or ECM-coated plastic culture surfaces, and a comparison was made between growth and function in the presence or absence of ECM. Melanocytes cultured on ECM-coated surfaces developed flatter and larger cell bodies and produced more melanin than melanocytes cultured on uncoated surfaces. In the presence of phorbol-myristate-acetate and cholera toxin, the rate of melanocyte replication was increased by ECM. In the absence of these mitogens, ECM significantly enhanced the adhesiveness of nonproliferating melanocytes. ECM had little or no effect on these parameters (morphology, tyrosinase activity, replication) in a pigmented human malignant melanoma cell line. These findings indicate that normal human epidermal pigment cells have the ability to recognize and respond to matrix signals, whereas this capacity appears to be absent in melanoma cells.

Cell Division↗
PubMed1988

Human melanoma cells: functional modulation by calciotropic hormones.

Four human melanoma cell lines were examined for their responsiveness to the hormones 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), calcitonin, and parathyroid hormone (1-34). Cells from each of the 4 lines contained high affinity binding sites for 1,25(OH)2D3. At high cell densities, binding of 1,25(OH)2D3 was diminished due to a decrease in receptor number with no apparent change in affinity. Preincubation with 1,25(OH)2D3 (10(-10) to 10(-8) M) increased tyrosinase activity 1.3- to 3.2-fold and 25-hydroxyvitamin D3-24-hydroxylase activity 1.4- to 10-fold. Human calcitonin (0.82 to 82.5 ng/well) raised the intracellular concentration of cyclic adenosine monophosphate 1.4- to 9.4-fold. Tyrosinase activity increased in response to calcitonin in 2 of the cell lines, decreased in the third, and showed no change in the fourth. Human parathyroid hormone (1-34) in concentrations of 1 to 10 ng/ml produced no significant changes in cyclic adenosine monophosphate accumulation, cell numbers, or tyrosinase activity in any of the cell lines. This study indicates that the phenotype of human melanoma cells can be modulated by the calciotropic hormones 1,25(OH)2D3 and calcitonin.

Calcitonin↗
PubMed1988

Human melanocytes as a target tissue for hormones: in vitro studies with 1 alpha-25, dihydroxyvitamin D3, alpha-melanocyte stimulating hormone, and beta-estradiol.

Clinical evidence exists which suggests that normal pigment cell (melanocyte) function is subject to hormonal influences, but the nature of these interactions at a cellular level is poorly understood. We have investigated the effects of the vitamin D-derived secosteroid hormone 1 alpha-25, dihydroxyvitamin D3 (1,25(OH)2D3), the pituitary-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH), and the sex steroid beta-estradiol on melanocytes cultured from normal human foreskin. Human melanocytes specifically internalized 1,25(OH)2D3 with high affinity (Kd 0.5-0.8 nM). Incubation with 1,25(OH)2D3 (10(-9) M) for 48 h resulted in a 100% increase in 25-hydroxyvitamin D3-24-hydroxylase activity and a 50% increase in tyrosinase activity. There was no significant effect of 1,25(OH)2D3 on intracellular cyclic adenosine monophosphate (cAMP). In contrast to 1,25(OH)2D3, alpha-MSH at a concentration of 5 X 10(-7) M caused a sevenfold increase in intracellular cAMP after 12 min but only a modest increase (less than 20%) in melanocyte tyrosinase activity after 48 h. Incubation with beta-estradiol for 24 h caused a dose-dependent increase in tyrosinase activity. The maximal response varied from 145%-213% of basal activity depending on the donor source. These results indicate that melanocytes from normal human foreskin in culture have the capacity to respond directly to several hormones. They also suggest that these cells form a useful model to study the effect of various hormones on pigment cell function.

Calcitriol↗
PubMed1986

Effects of catecholamines on plasma thyroid hormone levels in arctic charr, Salvelinus alpinus.

Plasma levels of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3) were measured in arctic charr at 2, 6, or 24 hr after single intraperitoneal injection of epinephrine (E) or norepinephrine (NE). At a dose of approximately 1 microgram/g body wt (sufficient to cause a submaximal dermal melanophore pallor response) plasma T4 was usually elevated at 2 hr, consistently depressed at 6 hr, and unaffected at 24 hr. There was no effect of E on plasma [125I]T4 kinetics or [125I]T4 5'-monodeiodination to [125I]T3. Plasma T3 showed no consistent response to E or NE at any sampling time. At an E dose of 4 ng/g body wt (probably sufficient to cause a physiological elevation in plasma E level), neither plasma T4 nor T3 levels were altered at 6 hr. Acute depression in plasma T4 by the high doses of E and NE may reflect a local neurotransmitter role of catecholamines in inhibiting thyroidal T4 release through action at thyroidal, hypophysial, or hypothalamic levels.

Animals↗
PubMed1984

Effects of various compounds on the accumulation of macrophages in mice.

The effects of different anti-inflammatory and anti-rheumatic compounds on the accumulation of macrophages in mice have been investigated. Glass coverslips were inserted subcutaneously and the cellular accumulation evaluated by measuring the surface covered by cells or the cellular potassium. Among the non-steroidal anti-inflammatory compounds tested, only niflumic acid and BW 755C were found active in this assay. Hydrocortisone, chloroquine and cyclophosphamide inhibited partially the migration of cells. Na- aurothiopropanol sulfonate, levamisole and methotrexate were inactive. MK 447 and d-penicillamine increased the accumulation of macrophages. The activity of the different substances is discussed in terms of their modes of action.

Animals↗
PubMed1983

Effects of calcium-antagonists on passive cutaneous anaphylaxis in the rat.

The actions of four Ca2+-antagonists (nifedipine, verapamil, diltiazem and D 600) were compared with those of four substances that are used clinically in treating asthma (theophylline, isoproterenol, disodium cromoglycate and clemastine), using the passive cutaneous anaphylaxis (PCA) reaction in the rat. Nifedipine, verapamil and diltiazem produced a partial, but dose-related inhibition of the PCA reaction. A slight, but significant inhibitory effect was also observed with D 600. Isoproterenol, theophylline and disodium cromoglycate also produced dose-related inhibition of the PCA reaction, their maximum effects being greater than those of the Ca2+-antagonists. As the histamine H1-antagonist clemastine was about as active as nifedipine, verapamil or diltiazem in inhibiting the PCA reaction, it seems possible that certain Ca2+-antagonists might be of value in treating allergic disorders in man.

Animals↗
PubMed1980

Pharmacological properties of a new anti-inflammatory agent: 2-(2-isopropyl-5-indanyl)propionic acid (UP 517-03).

2-(2-Isopropyl-5-indanyl)propionic acid (UP 517-03) is a new anti-inflammatory agent with marked analgesic and antipyretic properties. The anti-inflammatory potency is greater than that of phenylbutazone but lower than that of indometacin. This effect is observed also in adrenalectomized rats. The analgesic activity in the Randall and Selitto test is equipotent to that of indometacin, but this potency is lower in the other tests. In lowering brewer's yeast-induced fever in rats, UP 517-03 is as potent as indometacin and 10 times more effective than phenylbutazone. Considering from pharmacological index, UP 517-03 is tolerated as well as phenylbutazone and better than indometacin.

Analgesics↗
PubMedDate not supplied

In vitro and preclinical targeted alpha therapy for melanoma, breast, prostate and colorectal cancers.

Targeted alpha therapy (TAT) can inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotopes Tb-149 and Bi-213 were chelated to cancer specific monoclonal antibodies to form alpha-immunoconjugates (AIC) against melanoma, leukaemia, prostate and colorectal cancer, and to the plasminogen activator inhibitor type-2 (PAI2) to form alpha-PAI2 (API) against breast and prostate cancer. These conjugates were found to be highly stable, specific and cytotoxic in vitro. Melanoma and breast cancer tumour growth was observed in nude mouse models for untreated controls and non-specific AIC/API at 2 days post-subcutaneous inoculation of cancer cells. Complete inhibition of melanoma and breast cancer growth was found for local injections of AIC and API, respectively. Intra-lesional TAT of established melanoma showed that all melanomas regressed with 100 microCi injections of AIC. These results point to the potential application of local and systemic TAT in the management of metastatic cancer.

Alpha Particles↗