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Biomedical subjects

J Gwynne

Publications and source records attributed to J Gwynne.

12 recordsLinked to original sources
PubMed1994

Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in vivo.

JM216 is a novel antitumor platinum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neurotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma) and a human tumor model (PXN109T/C ovarian carcinoma xenograft) was studied in vivo. Single dose (q21d), once a day dosing for 5 consecutive days (q21d or q28d), and once a day dosing indefinitely (chronic daily dosing) administration schedules were compared. Against the murine ADJ/PC6 plasmacytoma, daily x5 administration improved the tolerance, antitumor potency, and therapeutic index of oral JM216, compared to single dose administration, whereas no advantage was found for fractionating cisplatin dosages. Against the PXN109T/C human ovarian carcinoma xenograft, oral JM216, given at dose levels delivering a equivalent total dose on single dose (200 mg/kg q21d), daily x5 (40 mg/kg/day q21d) and chronic daily dosing (9.5 mg/kg/d) schedules, showed superior tumor growth delays (55 +/- 15 days; P < 0.05) and maximal tumor regression (10 +/- 11% of initial tumor volume; P < 0.001) with the daily x5 schedule. Gastrointestinal toxicity (P < 0.05) and mild nephrotoxicity (P < 0.01) complicated the chronic daily dosing schedule, while leukopenia (P < 0.02) and thrombocytopenia (P < 0.01) were dose-limiting for the single dose and daily x5 administration, respectively. Peak plasma ultrafiltrate (PUF) platinum levels were below cytotoxic levels (PUF Cmax, 0.11 +/- 0.066 mg/l) at the maximally tolerable dose for the chronic dosing schedule (9.5 mg/kg). Peak PUF platinum levels did not increase significantly with a 5-fold increase in dosage from 40 mg/kg (PUF Cmax 1.5 +/- 0.11 mg/l) to 200 mg/kg (PUF Cmax, 2.4 +/- 0.44 mg/l; P > 0.05). In conclusion, these data demonstrate antitumor schedule dependency for oral JM216 in vivo, independently in two tumor model systems, and with nonlinear pharmacokinetics after its oral administration to mice. Optimal antitumor activity, tolerance, and pharmacokinetics occurred with daily x5 dosing, and this has prompted the clinical evaluation of this administration schedule.

Adenocarcinoma, Papillary↗
PubMed1992

Human ovarian-carcinoma cell lines and companion xenografts: a disease-oriented approach to new platinum anticancer drug discovery.

A disease-oriented approach to the discovery of novel platinum anticancer drugs has been established through the setting up of parallel human ovarian-carcinoma cell lines and xenografts. The correlation between in vitro and in vivo antitumour activity was determined for four reference platinum agents (cisplatin, carboplatin, iproplatin and tetraplatin) in eight companion lines. Two methods of assessing antitumour effect were used in vitro (tritiated thymidine incorporation and sulforhodamine B staining) and three were applied in vivo [28-day treated/control (T/C) ratio, growth delay and specific growth delay]. In vitro, large differences in cytotoxicity across the cell lines were observed for each drug. This was also reflected in the xenografts for cisplatin and carboplatin and, to a lesser extent, for iproplatin. A correlation analysis of in vitro vs in vivo data revealed a high, statistically significant positive correlation for cisplatin and a strong positive correlation for carboplatin. However, for the two platinum(IV) drugs, the correlation was less good. In particular, tetraplatin was markedly less active in vivo (showing a general lack of activity against all of the tumour lines) than its in vitro potency against the cell lines predicted, resulting in poor correlation coefficients. These human tumour panels may be valuable for the elucidation of both cellular/molecular and corresponding in vivo pharmacological mechanisms of platinum drug resistance. Moreover, the HX/62 and SKOV-3 tumour lines, which exhibit a level of intrinsic resistance to the four reference agents both in vitro and in vivo (and which were derived from patients who had not received prior platinum therapy), represent particularly useful evaluation models for the discovery of novel broad-spectrum platinum drugs.

Antineoplastic Agents↗
PubMed1991

Relationship between apolipoprotein E mRNA expression and tissue cholesterol content in rat adrenal gland.

Among extrahepatic tissues the adrenal gland has one of the highest concentrations of apoE mRNA and the highest rate of apoE synthesis. In the present investigation several previously described in vivo treatments were used to assess the relationship between apoE expression and cellular cholesterol in the rat adrenal gland. Treatment of rats with 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) to lower serum cholesterol concentration and deplete adrenal gland cholesterol content decreased adrenal gland apoE mRNA concentration. These adrenal responses were blocked by dexamethasone (DEX) suggesting that the effect of 4-APP occurred indirectly via stimulation of the adrenal gland by endogenous adrenocorticotrophic (ACTH). Relative to control rats, DEX treatment increased both adrenal gland cholesterol content and apoE mRNA concentration. Concurrent ACTH and DEX administration reduced both adrenal gland cholesterol content and apoE mRNA concentration relative to DEX-treated rats. ACTH administration also rapidly decreased adrenal gland apoE mRNA concentration and cholesterol content in rats pretreated with DEX. In all the above experiments, adrenal gland cholesterol content and apoE mRNA concentration were positively correlated (r = 0.78, P = 0.0001). In contrast, aminoglutethimide treatment, which blocks adrenal gland steroidogenesis and greatly increases adrenal gland cholesterol content, was without effect on apoE mRNA concentration. ACTH administration to rats treated with DEX + aminoglutethimide resulted in decreased adrenal apoE mRNA despite greatly increased adrenal cholesterol content. This uncoupling of adrenal gland cholesterol content and apoE mRNA concentration suggests that apoE mRNA expression and cellular cholesterol are regulated independently by ACTH.

Adrenal Glands↗
PubMed1989

Age-related changes in the haematology of female F344 rats.

As little comprehensive baseline data are available on age-related haematological changes in genetically-defined rat strains, the haematology of female F344 rats is described in animals sampled at 2, 4, 8, 20, 66 and 121 weeks of age. Values for Hb, RBC and PCV increased from 2 weeks of age to reach adult levels at 8 weeks, whereas MCV, MCH and reticulocyte counts were high initially but decreased to reach the adult range at 8 weeks. Between 66 and 121 weeks, reticulocyte counts were significantly increased and values for MCHC significantly decreased. Lymphocytes were the predominant white cell type in each age group. The absolute numbers of neutrophils and lymphocytes showed slight variations between 2 and 66 weeks and both cell types increased significantly between 66 and 121 weeks. Platelet counts showed no overall age-related trends. Fibrinogen values increased from 2 weeks of age to reach the adult level at 8 weeks. One animal of the 14 sampled at 121 weeks showed changes in the blood, liver and spleen consistent with a diagnosis of lymphoid leukaemia.

Aging↗
PubMed1986

The blood pressure response to unilateral adrenalectomy in primary aldosteronism.

The factors determining the outcome of blood pressure after removal of the aldosterone-secreting adenoma in primary aldosteronism are largely unknown. We have studied the results of surgery in 21 patients with this disorder, all of whom were investigated and treated in a single referral centre, and evaluated the contributions of clinical, biochemical and pathological factors to blood pressure outcome. Blood pressure before surgery was high (mean 210/121 mmHg), but after an average period of 5.4 years 12 patients (60 per cent) were considered by their primary physician not to require antihypertensive medication and a further seven had reduced drug requirements. In only two patients was arterial pressure unimproved by surgery. Blood pressure recordings within six months of surgery were not a good predictor of later levels. Of the clinical, electrolyte, hormone and pathological features assessed, only the systolic pressure before surgery, and abnormalities in the optic fundi, correlated statistically with final blood pressure ranking. There was no relationship between the severity of vascular changes in the adrenal or kidney biopsy tissue and final blood pressure. These results show that while the blood pressure response to the removal of a single adrenal adenoma is usually good, it is not possible to predict accurately the final blood pressure response using these criteria.

Adenoma↗
PubMed1985

Modulation of carcinogenesis in the urinary bladder by retinoids.

Bladder cancer has a 70% recurrence rate within five years and a high associated mortality. It commonly occurs in one or both of two predominant growth/behaviour patterns: either well-differentiated, relatively benign exophytic papillary lesions, or flat, poorly differentiated invasive carcinoma usually arising from carcinoma-in-situ. We have used the F344 rat treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as a model for the papillary disease, and the BBN-treated B6D2F1 mouse for flat, invasive bladder carcinoma. In the rat, carcinogenesis is a multistage process and several retinoids will delay or even halt the development of bladder cancer. Inhibition of carcinogenesis is not complete, but there is a consistent reduction in the time-related incidence of papillomas and carcinomas and a concomitant improvement in the overall differentiation of the urothelium. In the BBN/mouse model, retinoids also have anticarcinogenic activity but interpretation of the results is more complicated. Unlike the F344 rat, the B6D2F1 mouse has a non-uniform response to BBN; not all mice develop bladder cancer even after treatment with very high doses of BBN and in those that do, more than one mechanism of carcinogenesis may be involved. Individual retinoids differ markedly in their ability to modulate bladder carcinogenesis in rodents; the behaviour of one analogue cannot be predicted automatically from data obtained with another. Combined data from rodent trials in this and other laboratories have identified N-(4-hydroxyphenyl)retinamide (HPR) as the most anticarcinogenic retinoid tested so far for the rodent bladder. It is also less toxic in rodents and better tolerated in humans than either 13-cis-retinoic acid or etretinate, two retinoids currently used in dermatological practice. A prophylactic chemopreventive trial of HPR in bladder cancer patients starting in 1985 will be centered on the Middlesex Hospital, London.

Animals↗
PubMed1985

Retinoid toxicity.

The long-term effects of N-ethylretinamide (NER) on the haematology of the rat, and the dose-related effects of retinoids on lymphoid organs of the mouse and rat were investigated. Retinoid-induced long-bone changes were used to develop a method for quantifying skeletal effects. This technique was used to investigate the activity of five retinamides in inducing long-bone changes in the rat. The ability of non-steroidal anti-inflammatory compounds (NSAICs) to prevent retinoid-induced skeletal effects was examined, and preliminary investigations made into the mechanisms of retinoid-induced long-bone remodelling. NER-fed rats had reduced red blood cell counts and fibrinogen values. Retinoids caused dose-related proliferation of the spleen and lymph nodes in the mouse and to a lesser extent in the rat. They induced dose-related reductions in femoral diaphysis and medullary cavity diameters in both rats and mice. Aspirin prevented NER-induced changes of rat long bones, but subsequent studies indicated this effect may be closely dependent on the dose level of both the retinoid and NSAIC administered. Retinoids induce rapid long-bone remodelling in the rat which tends to revert on feeding a control diet, but remodelling processes are different in the young growing rat and the mature animal.

Animals↗
PubMed1984

Principal components analysis of haematological data from F344 rats with bladder cancer fed N-(ethyl)-all-trans-retinamide.

Several multivariate statistical methods are available which can alleviate the problems of analysing the large volumes of data generated from toxicological experiments. One such technique, principal components analysis, provides a method for exploring the relationships between a number of variables (such as blood parameters) and for eliminating redundant data if strong correlations exist between the characters. It also provides a method for clustering individuals, which may reveal similarities between animals in a treatment group or highlight individual 'outliers'. The application of principal components analysis to a set of haematological data from a trial evaluating the efficacy of a synthetic retinoid against carcinogen-induced bladder cancer in the rat has clearly shown, in two bivariate plots, that while some animals in the carcinogen-treated groups were normal, others were anaemic and that animals fed the synthetic retinoid and killed at 1 year had a microcytic anaemia. A full exploration of the data using conventional univariate statistical analysis would have involved at least 28 graphic representations of the data, as well as the interpretation of more than 130 means and SDs. Principal components analysis provides a valuable additional tool for the statistical analysis and exploration of toxicological data, but it must be used in conjunction with univariate or other multivariate methods if hypothesis testing is required. The use of multivariate techniques in toxicology may best be assessed by their practical application to toxicological data, and this paper presents such an evaluation with the aim of encouraging further exploration of the usefulness of principal components analysis. The raw data on which most analyses have been carried out are given.

Analysis of Variance↗
PubMed1975

The interaction of apoA-I from human high density lipoprotein with lysolecithin.

The binding of apoA-I to lysolecithin has been studied by fluorescence and circular dichroism. The influence of the conformation of apoA-I on its interaction with lysolecithin has also been evaluated. ApoA-I is bound to lysolecithin with an association greater than 10(7) whether apoA-I is native or highly unfolded in 1.8 M guanidinium hydrochloride. The association of apoA-I with lysolecithin results in an increase in secondary structure. A 25-residue fragment of apoA-I binds to lysolecithin equally strongly as the native molecule.

Apoproteins↗
PubMed1975

The molecular behavior of apoA-I in human high density lipoproteins.

The properties of apoA-I in human high density lipoprotein (1.063 smaller than d smaller than 1.210 gm per ml) have been examined by fluorescence and difference absorption spectroscopy, while the behavior of the total complement of apoproteins has been evaluated by far ultraviolet circular dichroism. Marked increases in stability to temperature, pH, and guanidine hydrochloride were observed for apoA-I in the native particle as compared to the isolated state.

Apoproteins↗