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Biomedical subjects

S B Kaye

Publications and source records attributed to S B Kaye.

At least 235 records · Page 13Linked to original sources
PubMed1990

The activity of verapamil as a resistance modifier in vitro in drug resistant human tumour cell lines is not stereospecific.

The L-isomer of verapamil is a more potent calcium antagonist than the D-isomer. We have examined the two stereoisomers of verapamil for their ability to increase the chemosensitivity in vitro of three drug resistant cell lines (2780AD, MCF7/AdrR and H69LX10). Neither racemic verapamil nor its individual isomers had any effect on the drug sensitivity of the parent cell lines (A2780, MCF7 and NCI-H69). Verapamil (6.6 microM) increased the sensitivity of all three resistant cell lines to Adriamycin by 10-12-fold. This activity was concentration dependent and was maximal at 6-7 microM. The increase in sensitivity was only 2-3-fold at 2 microM, the maximum plasma concentration achieved in patients. Both the D- and L-isomers of verapamil alone at 6.6 microM were as effective as racemic verapamil and the D-isomer demonstrated the same concentration dependent activity as racemic verapamil. The total cellular Adriamycin concentration of both 2780AD and MCF7/AdrR was increased by two-fold in the presence of verapamil (6.6 microM). Both D- and L-verapamil alone increased the amount of drug accumulated to the same extent as racemic verapamil. These results indicate that the resistance modification activity of verapamil is not stereospecific. Use of D-verapamil alone in patients could increase the maximum tolerated plasma concentrations of verapamil and thus D-verapamil may be a more effective resistance modifier in vivo than racemic verapamil.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Phase II trials with flavone acetic acid (NCS. 347512, LM975) in patients with advanced carcinoma of the breast, colon, head and neck and melanoma.

Phase II trials of flavone acetic acid have been performed in a total of 87 patients including 17 with advanced breast cancer, 23 with advanced colorectal cancer, 25 with advanced malignant melanoma and 22 with advanced head and neck cancer. Patients with colorectal cancer and melanoma had received no prior chemotherapy; in breast and head and neck cancer patients prior chemotherapy had been given with a median of 5 and 2 drugs respectively. The schedule used was a once-weekly regime, with a dose of 4.8 gms/m2 given as a 1 hour infusion, together with alkalinization (with i.v. sodium bicarbonate) given before and after FAA. Reassessment was performed after 6 weekly doses, although in 23 patients fewer than 6 doses were given, because of early disease progression in 15, and undue toxicity in 5. An additional 3 patients died within 72 hours of having received FAA and, although the precise cause of death in each case was not established, FAA toxicity could not be excluded. Treatment was generally manageable, the major manifestations of toxicity comprising uncomfortable warmth and flushes, nausea, diarrhoea, and visual complaints. Hypotension was also documented in 8 patients. No objective responses were seen in any of the patient sub-groups, although disease-stabilization was seen in 3 patients with breast cancer, 1 patient with advanced colorectal cancer, 2 patients with advanced melanoma and 4 patients with head and neck cancer. Further Phase II studies, using a higher dose of 8.6 gm/m2 over 6 hours once weekly, are currently in progress in Europe.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Distribution of doxorubicin to normal breast and tumour tissue in patients undergoing mastectomy.

Response to cytotoxic agents is assumed to be related to the concentration of drug achieved within tumour tissue. It is also often assumed that, given similar tissue concentrations of drug, normal tissues are less responsive to the same cytotoxic agents. This can partly be explained by the number of cells in normal tissues that are differentiated. These non dividing cells, in a stable testing phase of the cell cycle (G0) are less susceptible to cytotoxic damage. Little is actually known about the relationship between tumour drug concentrations and those in the tissue of the tumour-bearing organ. In this study, we compared doxorubicin concentrations in paired samples of tumour and normal breast tissue from 17 previously untreated women undergoing mastectomy. The relative cellularities of both specimens were estimated by measuring their DNA content. There was wide variation in intra-tumoural doxorubicin concentrations (range, 220-1,590 ng/g). Normal tissue also showed marked inter-patient variation (range, 81-1,000 ng/g). For a single patient the tumour drug concentrations were significantly higher than those in normal breast tissue (P less than 0.05), and tumour: normal tissue ratios ranged from 1.27 to 8.30. Where doxorubicin concentration was expressed in terms of the relative cellularity of the tissues, there was no significant difference between, drug concentrations in the tumour and those in normal breast tissue (tumour: normal ratios, 1.1:1.8). There was a significant correlation (r = 0.76, P less than 0.05) between peak serum values and tumour concentrations of drug. No correlation was found between drug concentrations achieved and the histological grade or oestrogen receptor status of the breast cancer.

Adult↗
PubMed1990

Relationship between the pharmacokinetics and toxicity of mitozolomide.

The cytotoxic drug mitozolomide has been found to cause unpredictably severe thrombocytopenia during phase I and II clinical trials. In an attempt to relate dose and pharmacokinetic parameters to toxicity, we measured plasma concentrations of mitozolomide in 14 patients with a range of malignancies. There were significant correlations (Spearman rank correlation test) between drug clearance and AUC and white blood cell nadir. The pharmacokinetic and toxicity data were not normally distributed; therefore, it was not possible to construct predictive nomograms for toxicity based on linear regression analysis.

Adult↗
PubMed1990

Phase I and pharmacokinetic study of intraperitoneal thioTEPA in patients with ovarian cancer.

A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy.

Adult↗
PubMed1990

Does lymphangiography have any role in the management of early non-seminomatous germ cell tumours?

Since 1980, 51 patients with non-seminomatous testicular germ cell tumours (NSGCT) and normal or equivocal initial computed tomography (CT) imaging have also had lymphography performed. Radiological records of these patients were reviewed to determine the extent to which lymphography (LAG) contributed to patient management. Forty-nine patients were retrospectively confirmed to have normal CT but of these 14 (29%) were considered to have nodal metastatic disease on lymphography. These patients and seven others with marker only evidence of tumour received chemotherapy and all remain disease-free. Six of thirty-six patients relapsed, but the incidence was not significantly higher in patients who did not undergo LAG (2 of 8:25%) than among those whose initial LAG was normal (4 of 28: 14%). All relapsing tumours achieved a complete remission with chemotherapy. We conclude that although LAG may have resulted in earlier treatment for some patients, several may have been overtreated on the basis of radiological abnormalities which did not represent metastatic disease. We believe that the success of salvage chemotherapy means that LAG may be safely abandoned as a staging procedure for NSGCT.

Humans↗
PubMed1990

Neurone specific enolase (NSE) in small cell lung cancer: a tumour marker of prognostic significance?

Pretreatment serum levels of neurone specific enolase (NSE) were measured in patients with small cell lung cancer (SCLC). Median values were significantly higher in patients with extensive compared with limited stage disease (48 ng ml-1 v. 17 ng ml-1: P less than 0.001). Serial NSE levels paralleled the clinical response to treatment. In 37 patients with limited SCLC, receiving identical chemotherapy, the pretreatment NSE level was of prognostic significance: with an approximate reduction in median survival of 10% for each 5 ng ml-1 incremental rise in NSE (P = 0.004).

Biomarkers, Tumor↗
PubMed1990

A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer.

Thirty-one patients were entered into a pilot study combining oral quinidine with epirubicin 100 mg m-2 as first line chemotherapy in advanced breast cancer. Three patients were treated with quinidine 1 g b.d., and developed symptoms of toxicity. Of eight subsequent patients treated with quinidine 500 mg b.d., two experienced tiredness and nausea and one severe oral toxicity with epirubicin. The remaining 20 patients received quinidine 250 mg b.d.; one developed cinchonism and one malaise, the remainder showing no excess toxicity compared with epirubicin alone. The median nadir WBC was similar with or without quinidine (2.3 vs 1.6 x 10(9) l-1) as was median nadir platelet count (175 vs 157 x 10(9) l-1). There was no evidence of significant cardiac toxicity. The median plasma quinidine level achieved was 5.6 mumol l-1 (range 2.1-22.1), which is within the range of concentrations which is effective in vitro at reversing experimental anthracycline resistance. A randomised controlled study is proposed to assess the impact of this potential modulation on the efficacy of epirubicin in advanced breast cancer.

Adult↗
PubMed1990

Long-term sequelae of treatment for testicular germ cell tumours.

Seventy-four patients previously treated in our department for germ cell tumour of the testis underwent a series of tests to determine the frequency of long-term therapeutic complications. All had received cisplatin-based chemotherapy as part of their treatment. There was a significant deterioration in renal function throughout the group. Eighteen (24%) had supine blood pressure greater than systolic 140 mmHg or diastolic 90 mmHg after treatment but hypertension did not correlate with renal impairment. Raynaud's phenomenon was common after chemotherapy (26/74) as was persistent sensory neuropathy (23/74). Although 34% had testosterone levels below the normal range, only six patients had a low free testosterone index with one testis still in situ; 18 patients have fathered children after chemotherapy. Approximately half of the patients completed a psychosexual questionnaire and some 30% of them admitted to sexual problems which they attributed to their treatment. Long-term sequelae of cisplatin-based chemotherapy for testicular malignancy are frequent and persistent, and follow-up of these patients should include prospective measurement of changes in blood pressure.

Adolescent↗
PubMed1990

P-glycoprotein expression in primary breast cancer detected by immunocytochemistry with two monoclonal antibodies.

We have investigated P-glycoprotein (P-gp) expression in samples of primary breast cancer from 29 patients before therapy. We employed immunohistochemical techniques using two monoclonal antibodies (C219 and MRK16) and an indirect alkaline phosphatase method. Heterogeneous expression in epithelial cells was detected with both C219 (21 of 29) and MRK16 (16 of 29). A surprising finding was P-glycoprotein expression in stromal cells with both C219 (26 of 29) and MRK16 (12 of 29). Our results suggest that significant levels of P-glycoprotein expression may be present in breast cancer before exposure to drugs associated with multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.

Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6 g m-2, above which dose-limiting hepatic toxicity was observed. Patient tolerance was significantly better using the 36 h infusion compared to patients receiving the drug by a 30 min infusion; in particular, there were no reports of nausea or vomiting. No responses were seen in these patients. Detailed pharmacokinetics were performed at 6 g m-2 comparing the 36 h and 30 min infusions in four patients. Parent drug AUC values were lower for the 36 h infusion, 67.8 micrograms ml-1 h-1 compared to 232 micrograms ml-1 h-1 for the 30 min infusion. AUC values for the 3-hydroxy metabolite were much higher following the 36 h infusion: 55.4 compared to 18.6 micrograms ml-1 h-1. In contrast, the amide metabolite was not detected following the 36 h infusion, but AUC values of 23 micrograms ml-1 h-1 were seen after the 30 min infusion. The mean peak plasma level was 72 micrograms ml-1 following 6 g m-2 given by a 30 min infusion compared to 2.8 micrograms ml-1 following the prolonged infusion. Clearance was higher following the 36 h infusion: 97.6 versus 24.4 l h-1.

Adult↗
PubMed1990

Low dose methotrexate and doxorubicin in hormone-resistant prostatic cancer. Scottish Urological Oncology Group.

A group of 24 patients, all of whom had progressive disease following initial hormone therapy for advanced prostatic carcinoma, were given intravenous methotrexate (30 mg/m2) and doxorubicin (15 mg/m2) at 2-week intervals for a planned 6-treatment course. Seventeen patients completed the full course. Assessment included "quality of life" criteria, using the subjective assessment of performance status, severity of pain and analgesic consumption. Over half of the patients improved in each of these modalities and 8 (33%) improved in all 3. As toxicity was acceptable, low dose chemotherapy may have a part to play in these patients who present a difficult management problem.

Aged↗
PubMed1990

Ocular shedding of herpes simplex virus.

The presence, frequency, and relationship of ocular and oral shedding of herpes simplex virus to previous herpes keratitis was investigated. This was to determine if a history of herpes keratitis predisposes to shedding of the herpes simplex virus into the tear film and/or mouth. Swabs were collected from the eyes and mouth of two groups of patients thrice weekly over a two- to four-month period. Group A comprised nine patients with a history of herpes labialis, group B 15 patients with a history of herpes keratitis. Herpes simplex virus type 1 was isolated from 1.33% of mouth specimens but was not identified in any of the ocular specimens. There was no significant difference between groups A and B in terms of ocular or oral shedding. Oral shedding appears to be independent of a previous herpes keratitis. The tear film is an unlikely source of virus in persons either with no history of herpes keratitis or between attacks in those patients with a history of previous herpes keratitis.

Adult↗
PubMed1990

Phase II study of recombinant human interferon-gamma in metastatic renal cell carcinoma.

The efficacy of a low-dose regimen of human recombinant interferon-gamma was studied in 40 patients with metastatic or locally advanced renal cell carcinoma. Patients received 100 micrograms/m2/day as an infusion over 4 h. The intention was to find an active but tolerable regimen as a basis for future combination treatments with other cytokines or cytotoxic drugs. Activity of this low-dose schedule had been reported. In the absence of rapid progression, treatment was given for at least 3 months, and in case of stable disease it was continued for prolonged periods in order not to miss late remissions. Toxicity was generally mild, with fever and constitutional symptoms predominating. Therapeutic efficacy was low with only one partial remission. Three patients had stable disease over 6, 9, and 15 months. This low-dose schedule cannot be recommended for the treatment of renal cell cancer.

Adult↗