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Biomedical subjects

G Atassi

Publications and source records attributed to G Atassi.

At least 163 records · Page 9Linked to original sources
PubMed1976

Potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea by amphotericin B in murine ependymoblastoma.

This paper reports the potentiation of the therapeutic effect of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) by amphotericin B (AMB) in s.c. transplanted murine ependymoblastoma 01B111. The rate of 2-month cures was 6% when tumors were treated 10 to 12 days after transplantation by a single 6 i.m. injection of 2.5 mg of CCNU per kg and reached 15% with 10 mg of CCNU per kg. When 25 mg of AMB per kg were given i.p. 10 hr prior to CCNU, the respective figures increased to 18 and 58%, the differences being significant at 5 and 1%. A single dose of 25 mg of AMB per kg given alone did not affect tumor growth. Radioactivity per g of tumor was measured 30, 60, and 120 min after injection of [14C]CCNU in total tissue, chloroform:methanol (2:1, v/v) extract, and CCNU isolated by thin-layer chromatography. No difference was found between animals treated with 25 mg of AMB per kg and controls. The inhibition of DNA synthesis, measured 24 hr after the administration of CCNU and 2 hr after the injection of [3H]thymidine, was almost optimal with 5 mg of CCNU per kg. The inhibition caused by 1 mg of CCNU per kg was not enhanced by AMB. Thus, the potentiation of CCNU by AMB does not seem attributable to an increased permeability of the tumor to CCNU or to an enhancement of the inhibition of DNA synthesis, at least in murine ependymoblastoma.

Amphotericin B↗
PubMedDate not supplied

A new method for the purification of cytochrome-P450 from human liver microsomes.

A procedure for the solubilization and purification of cytochrome-P450 (cyt-P450) from human liver microsomes is described. Successive treatment of microsomes with protease XXVII and 3-(3-cholamidopropyl)dimethylammoniopropanesulphonic acid gave a solubilized cyt-P450 in more than 80% yield and with a three-fold increase in specific activity. With this treatment it was possible to eliminate 80% of cytochrome-b5 and 75% of NADPH cyt-P450 reductase. The solubilized cyt-P450 was filtered on a Sephacryl-200 column and then subjected to high performance liquid chromatography with a Mono-P column (chromatofocussing). The recovery of separated cyt-P450 was about 50% with a specific activity of 11.5 nmol cyt-P450/mg protein. Also with this technique it was possible to determine the isoelectric points of cyt-P450. These results allowed us to confirm the usefulness of our method, for the study the cyt-P450 from surgical biopsies.

Biopsy↗
PubMedDate not supplied

Ineffectiveness of inicarone, a fibrinolytic agent, alone or in combination with chemotherapeutic agents on spontaneously metastasizing murine tumours.

The effect of inicarone (L7035), a potent fibrinolytic, alone or in combination, was investigated on spontaneously metastasizing Lewis lung carcinoma (implanted intramuscularly) to verify whether it could prevent the formation of metastases. After intraperitoneal and oral administration, inicarone did not show any cytotoxicity since the survival of animals was not prolonged. Its activity was compared to that of warfarin, an anticoagulant: both drugs were inactive when administered in curative treatment and inicarone even enhanced the number of lung metastases. When administered in combination with cyclophosphamide, an antiproliferative agent, inicarone did not induce any synergism or antagonism, but this combination did not inhibit tumour growth or metastasis spreading. Moreover, when inicarone was combined with a potent antimetastatic agent, Nocodazole, it was shown to be in competition with the latter agent and totally overshadowed its activity; since inicarone had no antimetastatic effect, the number of metastases rose dramatically.

Animals↗
PubMedDate not supplied

Investigation of a new murine model of regional lymph node metastasis: characteristics of the model and applications.

The RC tumor, originally a renal adenocarcinoma very sensitive to different classes of chemotherapeutic agents, maintained in CDF 1 mice, was examined for its ability to metastasize. When inoculated into the foot (with 10(7) tumor cells), bulky metastases developed in the popliteal and para-aortic lymph nodes, in a constant and reproducible pattern, producing a massive microscopic invasion of the liver, the lungs and the spleen. The antigenicity tests demonstrated a low immunogenicity of the tumor. Chemotherapy assays showed that adriamycin and vincristine were effective against metastatic dissemination when administered early after tumor cell inoculation and principally when combined with excision of the tumor-bearing leg. The RC model appears to be suitable for the study of lymph node metastasis and could be used in chemotherapy trials of new drugs potentially effective against metastases of the lymphatic system.

Adenocarcinoma↗
PubMedDate not supplied

A new algorithm for computing the parameters of linear compartment models in pharmacokinetics.

A new algorithm (FADHA) for computing pharmacokinetic parameter estimates has been developed. This technique is based on the simplex method which is used to minimize a nonlinear cost function. An important property of this program is that the convergence is ensured contrary to the well-known linear or nonlinear least-squares regression analysis which lead to a lack of convergence or to a false one. Two investigations of the comparative performances of FADHA program and other algorithms were undertaken (hexamethylmelamine and Piracetam pharmacokinetics). Least square analysis of data yielded biased estimates whereas FADHA estimates were unbiased and more precise. This new technique, takes into account all the possible observation errors and uses the concept of a weighting function rather than weights as such.

Altretamine↗
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

Antitumoral cyclic peptide analogues of chlamydocin.

A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

Amino Acid Sequence↗
PubMedDate not supplied

Synthesis and cytotoxic activity of 2-dialkylaminoethylamino substituted xanthenone and thioxanthenone derivatives.

The synthesis and biological evaluation of some new pyranoxanthenones and pyranothioxanthenones, substituted with flexible amino side-chains, and their evaluation as potential antitumor agents is described. The cytotoxic activity of the compounds and their eventual selective effect on a phase of the cell cycle were evaluated in vitro, using the murine lymphocytic L1210 leukemia cell line. The new aminoderivatives exhibited highly potent cytotoxicity against the leukemia L1210 cell line when compared to acronycine. All the compounds induced a partial accumulation of cells in the G2 + M phase of the cell cycle.

Animals↗
PubMedDate not supplied

Characterization of TNP-470-induced modifications to cell functions in HUVEC and cancer cells.

The aim of the present work is to characterize (both in vitro and in vivo) the influence of TNP-470 on different cell functions involved in angiogenesis and, more particularly, on endothelial cell growth, cell migration and vessel formation. In addition, a possible direct anti-tumor activity was investigated. To this end, we made use in vitro of human umbilical cord endothelial vein (HUVEC) cells and two human cancer cell lines. The TNP-470 effects on the growth of cancer cell lines were compared to those of Taxol (an inhibitor of microtubule depolymerization), a cytotoxic reference which also displays strong antiogenic activity at low (non-toxic) doses. The in vitro effects were characterized on the mouse mammary MXT adenocarcinoma, on which we also characterized the influence of three clinically active anti-tumor compounds (as cytotoxic references). The purpose of this part of the study was to determine the actual TNP-470-related anti-tumor activity and to evaluate the possible toxic side-effects at the doses at which this compound induces tumor growth inhibition. These investigations were completed by analyzing the TNP-470 effects on HUVEC cell motility and in vitro and in vivo vessel formation. The results show that in vitro, TNP-470 inhibited the growth not only of HUVEC, but also of neoplastic cells. Furthermore, TNP-470 clearly inhibited in vitro endothelial cell motility (p<10(-5)). However, it had only a minor effect (p=0.02) on the formation of HUVEC cell networks on Matrigel(R). In vivo, TNP-470 was able to inhibit tumor growth (on the MXT model) at a dose (50 mg/kg) associated with toxic side-effects. Histological examination showed a significant inhibition of vessel formation (p<0.001) at high (toxic) and intermediary (non-toxic) doses (50 and 20 mg/kg). However, we also observed that TNP-470 stimulated lymphocyte proliferation. Thus, care must be taken with the TNP-470 compound in combination with other anti-tumoral agents in order to avoid certain unfortunate clinical complications.

Adenocarcinoma↗
PubMedDate not supplied

[Conditions for analysis of cytochrome p-450 activity in human liver microsomes].

Multiples forms of CYT-P450 have been isolated from human liver microsomes. The distribution of CYT-P450 could be correlated with pathologic and influence the individual's response to therapeutic drugs and susceptibility to the toxic and cancerogenic effects of environmental pollutants. The aim of the this work is to determine the amounts of CYT-P450's in small samples from human liver such as biopsies and eventually to correlate them with pathology. For these reasons, tests providing informations about the distribution of CYT-P450 in individual subjects are very important. In this study we have reviewed the method for measuring the activity of CYT-P450 and the dosage of Benzopyrene hydroxylase. We modified some of these methods for the study of CYT-P450 from human liver microsomes.

Cytochrome P-450 Enzyme System↗
PubMedDate not supplied

Characterization of the pharmacological antitumor effects of S 12363, a new vinca alkaloid.

S 12363 is a new highly potent vinca alkaloid derivative characterized by the grafting of an a-aminophosphonate, bioisoster of the valine, at the C23 position of O4-deacetyl vinblastine. Using a cell image processor Samba 200 (System for Analytical Microscopic Biomedical Applications), we have studied the effect of S 12363 on cell proliferation of four mammary (MXT, MCF-7, T47-D and MDA-MB231) and two melanoma (HBL and DRD 3) tumor cell lines, and on cell cycle kinetic parameters on human T47-D and HBL tumor cell lines. S 12363 significantly inhibited the growth of these 6 tumor cell lines in a time- and concentration-dependent manner. Three concentrations were tested for 24, 48, 72 and 96 hours incubation times. The human breast T47-D, MCF-7 and melanoma DRD3 and HBL tumor cells were the most sensitive to S 12363. This compound was effective at all doses tested (0.1, 1 and 10 ng/ml) after at least a 24 hour incubation period. The murine MXT and human MDA-MB231 tumor cells were about 10 fold less sensitive than the other cell lines. S 12363 disturbed the cell cycle of T47-D and HBL cell lines and induced a significant accumulation of cells in the G2 + M phases to the detriment of the G0 + G1 phases. The antitumor activity of S 12363 was confirmed in vivo on 2 disseminated murine tumor models, i.e. P388 leukemia implanted subcutaneously and M5076 reticulum-cell sarcoma inoculated intraperitoneally. S 12363 was at least as active as reference compounds vinblastine or vincristine with active doses 5 to 20 times lower.

Animals↗