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Biomedical subjects

S B Kaye

Publications and source records attributed to S B Kaye.

At least 253 records · Page 14Linked to original sources
PubMed1989

Effects of the pH dependence of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide-formazan absorption on chemosensitivity determined by a novel tetrazolium-based assay.

The tetrazolium dye, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), is reduced by live but not dead cells, and this reaction is used as the end point in a rapid drug-screening assay. It can also be used for accurate determinations of drug sensitivity but only if a quantitative relationship is established between cell number and MTT-formazan production. We have shown that reduction of MTT to MTT-formazan by cells is dependent on the amount of MTT in the incubation medium. The concentration required to give maximal MTT-formazan production differs widely between cell lines. The absorption spectrum of MTT-formazan varies with cell number and with pH. At a low cell density or a high pH, the absorption maximum is at a wavelength of 560 to 570 nm. However, at a high cell density or a low pH, there are two absorption maxima; one at 510 nm and a second at about 570 nm. Measurements of absorbance at 570 nm underestimate MTT-formazan production and, hence, cell number at high cell densities. This error can result in a 10-fold underestimation of chemosensitivity. Addition of a buffer at pH 10.5 to the solubilized MTT-formazan product can overcome the effects of both cell density and culture medium on the absorption spectrum. Provided that sufficient MTT is used and the pH of the MTT-formazan product is controlled, dye reduction can be used to estimate cell numbers in a simple chemosensitivity assay the results of which agree well with a commonly used clonogenic assay.

Azo Compounds↗
PubMed1989

Characterization of the major metabolites of flavone acetic acid and comparison of their disposition in humans and mice.

Flavone acetic acid represents a novel chemical structure currently undergoing clinical investigation. Broad spectrum activity has been observed in preclinical animal screens, but at doses close to toxic in mice. Phase I clinical trials have established that equivalent plasma drug levels can be achieved in humans, but to date Phase II trials have not demonstrated significant activity in a range of tumor types. Little is known about the drug's biotransformation, although metabolites have been implicated in proposed mechanisms of action. In this paper, we have purified the two major human metabolites present in urine (also the only two metabolites detected in plasma) and characterized their structure, chemical properties, activity, and pharmacokinetics. Metabolite 1 (M1) was a glucuronide conjugated to the 8-acetic acid grouping (Mr 456), was chemically labile, and showed a strong tendency to undergo chemical rearrangement at mildly alkaline pH. Metabolite 2 (M2) was also a glucuronide (Mr 456) but appeared to be an unusual isomer of M1. Both were noncytotoxic. In patients, biotransformation represented the predominant mechanism of drug clearance with as much as 80% of a low dose (0.5 g/m2) recovered in urine as M1 and M2 after only 6 h. At high dose (4.8 to 8.6 g/m2, 1- to 6-h infusion) the appearance of peak concentrations of metabolites in plasma and urine was delayed, apparently due to saturation of glucuronidation pathways. This resulted in an overall reduction in drug clearance by 3- to 4-fold. Mice cleared flavone acetic acid much more slowly than patients (289 ml/h/m2 after 600 mg/m2 i.p. versus 2.3 liters/h/m2 after 4.8 g/m2-1-h i.v. infusion) without producing M1 or M2. A different metabolite, exhibiting characteristics of a conjugate, was detected at low concentrations in plasma, tissues, and tumor. Extensive metabolism to inactive products followed by their rapid clearance may contribute to the lack of activity so far seen in humans.

Animals↗
PubMed1989

Phase I clinical and pharmacokinetic study of LY 195448.

LY 195448 is a phenethanolamine that has shown anti-tumour activity in a range of murine tumour models, although its mechanism of action is unknown. Pre-clinical studies have indicated the absence of "standard" side effects such as myelosuppression and gastrointestinal toxicity. The present phase I trial was carried out in nine patients at doses ranging up to 133 mg/m2. The major toxicities up to that dose were mild, reversible hypotension, tachycardia and tremor. No haematological or biochemical toxicity was observed. Murine pharmacokinetics were assessed at a dose level that was effective in experimental tumours and compared with human pharmacokinetic parameters derived from this study. The results indicated the clinical possibility of reaching peak drug levels associated with experimental activity. However, no responses were seen at the doses used. This study was terminated prior to its completion due to an unexplained loss of activity against murine tumours since September 1987. No significant loss of the in vitro anti-mitotic activity originally reported by Boder et al. [3] was observed. Possible reasons for the apparent loss of in vivo activity have been intensively investigated, but no cause has been determined. Therefore, clinical trials with LY 195448 have been discontinued.

Adult↗
PubMed1989

The relative effectiveness of analogues of cisplatin in the experimental chemotherapy of human non-small-cell lung cancer and neuroblastoma grown as multicellular spheroids.

We compared cisplatin (cis-DDP) and two of its analogues, carboplatin (JM8, CBDCA) and iproplatin (JM9, CHIP) for their ability to retard the growth of multicellular tumour spheroids. The spheroids were derived from two human tumours, a neuroblastoma and a non-small-cell lung cancer. To produce a given level of regrowth delay in lung cancer spheroids, carboplatin and iproplatin were required at concentrations approximately 10 times that of cis-DDP. In the neuroblastoma spheroid experiments, iproplatin and cis-DDP produced the same level of regrowth delay when iproplatin was present at a concentration greater than 10 times that of cis-DDP. Carboplatin also required much higher concentrations than cis-DDP to produce equivalent regrowth delay in neuroblastoma. The dose-response curve produced by carboplatin on neuroblastoma spheroids displayed a pronounced shoulder in the low-dose region; this phenomenon was not seen with cis-DDP. These findings may have implications for the clinical use of these drugs and in particular would support a role for carboplatin in the treatment of lung cancer, since total free-drug exposure of patients to carboplatin may be up to 16-fold greater than with cis-DDP. However, one must be cautious about generalizing on the basis of results from only two cell lines as well as applying in vitro data to clinical situations.

Carboplatin↗
PubMed1989

Could interspecies differences in the protein binding of flavone acetic acid contribute to the failure to predict lack of efficacy in patients?

We investigated the differences in plasma protein binding of flavone acetic acid (FAA) in mice and men in an attempt to explain the inter-species differences in response. In vitro data indicate both qualitative and quantitative differences in FAA protein binding: approximately 80% is bound in humans, with two different types of binding site identified; in mice, 70% is bound and only one binding site could be described. Protein binding is dose-dependent in both species. Plasma samples from 20 patients receiving FAA showed that most achieved levels that would be active in mice. We conclude that these differences in protein binding are insufficient to explain totally the observed differences in response.

Animals↗
PubMed1989

Excision of residual masses after platinum based chemotherapy for non-seminomatous germ cell tumours.

Between January 1980 and June 1987, 42 patients receiving platinum based combination chemotherapy for advanced non-seminomatous germ cell tumours had residual masses, detected by computed tomography, after four or six treatment courses without tumour marker evidence of active disease. Resection of retroperitoneal (n = 32), pulmonary (n = 4) or thoracoabdominal (n = 2) disease revealed residual malignancy in nine patients (21%), differentiated teratoma in 14 (33%) and fibrosis or necrosis in 15 (36%). Laparotomy showed no evidence of a mass in four instances. Of the 42 patients, 14 had malignant teratoma undifferentiated in the primary tumour only one of whom (7%) had evidence of malignancy in the specimen resected post-chemotherapy. Conversely, six of 15 patients (40%) whose primary tumour was malignant teratoma intermediate had residual malignant tissue after treatment. With a median follow up of 36 months from post-chemotherapy surgery, 36 patients (86%) are continuously disease-free. Relapses occurred in one of nine patients with residual malignancy (11%), three of 14 with differentiated teratoma (21%), one of 15 with necrosis or fibrosis (7%) and in one patient who had a normal laparotomy. Four patients have died from their tumours, but two are currently disease-free following further surgery and chemotherapy for relapse. Neither primary nor post-chemotherapy histology was predictive of relapse, and although relapse was numerically more common in patients whose residual mass was incompletely excised (three of 12), this was not statistically significant.

Adolescent↗
PubMed1989

The prognostic value of a response to chemotherapy given before radiotherapy in advanced cancer of cervix.

Forty patients with stage III and 15 patients with stage IVa carcinoma of cervix have been treated with two pulses of cisplatin, vincristine and bleomycin combination chemotherapy before full dose radical radiotherapy. Twenty-seven of 51 (53%, 95% confidence interval 40-67%) had an objective response to chemotherapy and all chemotherapy responders had a complete response to radiotherapy. The actuarial survival at 24 months of responders to chemotherapy is 71% against 37% for non-responders. The responding patients had an estimated reduction in mortality to 36% (P = 0.014, 95% CI 15-81%) of that of the non-responders to chemotherapy. The incidence of tumour recurrence or distant metastases showed a similar reduction to 34% (P = 0.006, 95% CI 14-73%) of that of the non-responders. The data strongly suggest that response to chemotherapy in the initial treatment of advanced cervical cancer is associated with an improvement in survival following subsequent radical radiotherapy.

Adult↗
PubMed1989

The prism bar--Prentice and frontal positions.

The prism cover test has been in use for many years for measuring ocular alignment. The measurements obtained are used for both calculating the amount of correction needed in strabismus surgery, and monitoring any change in ocular alignment with recovery from muscle imbalance. Variability may arise from its use in either the frontal position or the Prentice position. Most prism bars used in the United Kingdom are calibrated for use in the Prentice position. Inaccurate results arise when a prism bar is used in a position for which it is not calibrated. The theoretical calculation for adjusting measurements obtained in the frontal position with prisms calibrated for use in the Prentice position was assessed clinically. A new modified equation is proposed incorporating practical aspects of performing the prism cover test. A table of values is included to assist in determining the necessary adjustment, so allowing for a more reliable assessment.

Adolescent↗
PubMed1989

Chart for visual acuity screening.

The statistical basis underlying the use of several visual acuity charts is examined. A new chart which offers theoretical and practical advantages for visual acuity screening is described.

Humans↗