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Biomedical subjects

M Hanocq

Publications and source records attributed to M Hanocq.

52 records · Page 3Linked to original sources
PubMedDate not supplied

Pharmacokinetics of daunorubicin and daunorubicinol in plasma, P388 and B16 tumours. Comparison with in vitro cytotoxicity data.

The comparison of pharmacokinetics of DNR in mouse plasma, in the DNR naturally resistant B16 melanoma and in the DNR naturally sensitive P388 leukemia showed that there is no direct correlation between total concentrations of this drug in tumours and the sensitivity resistance of these tissues. A finding which demonstrates the inadequacy of distribution models to select new potential anticancer drugs. Cytotoxicity of DNR and its metabolites to B16 melanoma and P388 leukemia cell lines were determined in vitro. Calculated inhibitory concentrations 50 (IC50) were compared to maximal concentrations determined by pharmacokinetic studies. In all cases in vitro IC50 were lower than Cmax values. Moreover, resistant cells in vivo were found to be sensitive to DNR and metabolites when they are propagated in vitro. Tissue concentrations, as well as in vitro data, were fitted to appropriate models by an original program (FADHA) which uses the simplex method to minimize a non-linear cost function. Best fit models were chosen by statistical criteria.

Analysis of Variance↗
PubMedDate not supplied

Pharmacokinetic study of orally administered zinc in humans: evidence for an enteral recirculation.

Starting from the experimental design of the established 'Zinc Tolerance Tests', the absorption and distribution of the essential trace element zinc in humans was investigated in 10 subjects by performing a pharmacokinetic study of the serum zinc profile after oral administration of a pharmacological dose of the metal, i.e. 0.69 mmol (45 mg) zinc as ZnSO4.7 H2O. The adopted experimental conditions include frequent measurements of serum concentrations, a total investigation time of 8 h after ingestion, and a correction of basal zinc levels taking into account the circadian variation. Rebound effects were evidenced in the time versus concentration curves showing a regular recycling of the element in the digestive tract. Estimation of the parameters by an original method allowed us to calculate the characteristics of the cycles. The first one occurred after 1.4 h, before the time needed for appearance of the maximum concentration which was around 2.3 h, and exhibited mean reabsorption of 70% of administered dose. The subsequent ones, maximum 5 during the investigation period, appeared at regular intervals of approximately 1.2 h, with a decrease in the quantity reabsorbed. These observations are consistent with the previously reported endogenous secretion of zinc, a physiological mechanism contributing to zinc homeostasis.

Absorption↗
PubMedDate not supplied

In vitro cytotoxicity of hexamethylmelamine (HMM) and its derivatives.

The cytotoxicity of hexamethylmelamine (HMM) and its metabolites was investigated in three murine cell lines: one in vitro naturally sensitive to HMM (RC) and two in vivo naturally resistant (P388 and P388D1). The percentage of viable cells was determined both by the in situ reduction of a tetrazolium salt (MTT assay) and by the uptake of labelled thymidine into DNA (3HTdR assay). Short (1h) and long (48h) exposures of cells to drugs were considered. In all experimental conditions used, HMM was found to be inactive, whereas its hydroxylated metabolite hydroxymethylpentamethylmelamine (HMPMM) and one analog N, N 'dihydroxymethyltetramethylmelamine (DHTMM) were found to be cytotoxic. The results further indicated that HMM must be metabolized before it can exert its cytotoxic effect. The activity of HMPMM and DHTMM was found unlikely to be related to extracellular or intracellular release of formaldehyde.

Altretamine↗
PubMedDate not supplied

Comparison of two cytotoxicity assays--tetrazolium derivative reduction (MTT) and tritiated thymidine uptake--on three malignant mouse cell lines using chemotherapeutic agents and investigational drugs.

Two different techniques [reduction of a tetrazolium derivative (MTT) and 3HTdR uptake assays] were compared in order to evaluate the cytotoxic effects of different chemotherapeutic agents in vitro. The cytotoxicities of Melphalan, hexamethylmelamine and seven derivatives, and daunorubicin were measured on P388D1 mouse macrophage-like cell line, RC mouse renal carcinoma cell line, and B16 mouse melanoma cell lines. Growth inhibition was determined after one hour as well as after continuous (48 hours) exposure to drugs. The IC50 was calculated using an appropriate algorithm (FADHA) which allowed within and between run variabilities to be taken into account. Optimal conditions had to be elucidated for culture conditions before assay: number of cells/well and assay duration for each line. The MTT and 3HTdR uptake assays were found to be similar in terms of sensitivity and reproducibility, both for adherent and floating cell lines. However, the MTT assay has the advantages of low cost and time saving. It also avoids problems related to radioactivity manipulation and counting. Both techniques rank the same chemicals as active or inactive. The algorithm Fadha was found to be a very powerful mathematical tool for comparing the IC50 values obtained by both assays.

Animals↗
PubMedDate not supplied

Compared cytotoxicity effects of five anticancer drugs on human (HBL) and mouse (B16) melanoma cells in vitro.

In order to assess the potential interest of replacing the murine cell lines by human cell lines for in vitro cytotoxic assays, the sensitivity and the selectivity of the murine B16 and the human HBL melanomas to five chemotherapeutic drugs were investigated in vitro. The cytotoxicities of Melphalan, Daunorubicin (DNR), Hexamethylmelamine (HMM), Hydroxymethylpentamethylmelamine (HMPMM), and Dihydroxymethyltetramethylmelamine (DHTMM), 2 HMM derivatives, were measured in the two cell lines using two different techniques: reduction of a tetrazolium derivative (MTT) and tritiated thymidine uptake into DNA. The cytotoxicity at inhibitory concentration 50 (IC50) was determined after one hour as well as after 2 days exposure of cell after one hour as well as after 2 days exposure of cells to each drug. The results indicate that the HBL human melanoma was generally more sensitive to Melphalan and DHTMM than the B16 murine melanoma cells as far as the IC50 was concerned. In contrast, no difference of sensitivity was found to DNR and DHTMM. HMM was found to be inactive in both cell lines. The analysis of variance on IC50 values showed that the sensitivity of murine and human melanoma cell lines to drugs was statistically different. Despite the identical selectivity of the two cell lines, two promising observations can be made as far as the comparison of the two cell lines is concerned: 1) the higher sensitivity of HBL human cell line to Melphalan in the in vitro assays and 2) the slightly lower sensitivity of HBL to DNR, a drug without clinical activity against human melanoma.

Analysis of Variance↗
PubMedDate not supplied

Tumor pharmacokinetics of hexamethylmelamine in CDF1 mice bearing P388 leukemia.

The pharmacokinetics and metabolism of hexamethylmelamine (HMM) have been studied in CDF1, mice bearing P388 leukemia. The results obtained for this tumor, which is naturally resistant to HMM, were compared with data on HMM sensitive RC tumor and plasma. The pharmacokinetic parameters, estimated by an original algorithm (FADHA), indicated that HMM Cmax and AUC were very high in RC and P388 tumors as compared to plasma values, but could not be directly correlated with HMM activity. Hydroxymethylpentamethylmelamine (HMPMM), a potentially anticancer metabolite of HMM, was easily detected in P388 leukemia while very poorly detected in RC tissue. This finding led us to make the hypothesis that HMM activity could correlate with HMPMM ability to interact irreversibly with DNA and proteins in tumors.

Altretamine↗
PubMedDate not supplied

[Adjustment of the dose-effect curve by means of an original algorithm. Application to the study of cytotoxicity in vitro].

Dose-effect curves were fitted in optimizing a non-linear cost function by the simplex method. Two kinds of mathematical functions (Gompertz and Von Bertalanffy) and some weighting processes were studied. In each case a statistical analysis was carried out to choose the curve which is best fitted to experimental data. From the best curve, the efficient doses were calculated. This work was illustrated by cytotoxicity studies concerning melphalan and pyrrolidin.

Algorithms↗
PubMedDate not supplied

[Some factors influencing the bioavailability of zinc in oral pharmaceutical dosage forms].

Absorption and distribution of zinc in 6 dosage forms were determined in 10 subjects by performing a pharmacokinetic study of the serum zinc profile after oral administration of a dose corresponding to 45 mg elemental zinc. The aim of this study was to document the influence on zinc bioavailability of factors such as the chemical form of zinc, the pharmaceutical form, and the division of the administered dose. The pharmacokinetic parameters indicate for gelatin capsules without excipients taken in a non divided dose better performances for zinc gluconate in comparison to zinc sulfate. Concerning the pharmaceutical form, little difference is observed between an aqueous solution and a gelatin capsule for zinc sulfate and a non divided dose; on the contrary, a commercial gelatin capsule containing zinc gluconate with various excipients show better performances than gastro-resistant tablets when zinc intake is 3 times 15 mg. Finally, the division in 3 parts of the dose of zinc sulfate given in gelatin capsules very significantly improves zinc absorption. These results demonstrate the interest of the developed pharmacokinetic method in the assessment of zinc bioavailability in different pharmaceutical dosage forms.

Administration, Oral↗
PubMedDate not supplied

Evidence of difference between cytotoxicity, cell cycle and morphonuclear effects of polyamines on sensitive and multidrug resistant P388 cell lines.

This paper reports studies on the influence of multidrug resistance (MDR) on the mechanism of polyamine toxicity. The effects of putrescine (PUT), spermidine (SPD) and spermine (SPM) on morphonuclear parameters and cell cycle were studied by means of digital cell image analysis. This reveals that only SPD and SPM condense chromatin inducing a strong decrease in the nuclear area and a cell-cycle arrest in phase G2 in P388/s and the two MDR sublines. A significant difference was observed between the sensitivity of the two phenotypes, which confirms results obtained by means of a microculture tetrazolium test which showed that SPD and SPM were highly, but very differently, cytotoxic on sensitive and MDR sublines, unlike PUT, which was not toxic. This encourages us to study more thoroughly possible differences in polyamine metabolic enzymes and uptake in these cells, to enable us to acquire a better understanding of the impact of MDR phenotype on the polyamine pathway.

Animals↗