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Biomedical subjects

G Atassi

Publications and source records attributed to G Atassi.

180 records · Page 10Linked to original sources
PubMedDate not supplied

Evaluation of a new nitrosoureido water-soluble sugar, ecomustine or CY 233 (NSC 609224), on human xenografts.

Because of its wide spectrum of activity against murine models regardless of the route of administration, CY 233 (NSC 609624) was investigated in human tumours xenografted in nude mice, namely one amelanotic melanoma, MeXF 274, and three colon adenocarcinomas, i.e. CXF 233, CXF 243 and CXF 609. CY 233 was highly active against the MeXF 274 melanoma and produced a complete response on day 14 at 20 mg/kg given i.v. on days 0 and 7. After three intermittent i.v. injections of 10 mg/kg, it produced a partial response of long duration against the colon adenocarcinoma CXF 243. The interesting fact that resistant lines responded to CY 233 warrants further investigation of other schedules of treatment and of the sensitivity profile of CY 233 in a wider panel of tumour xenografts.

Adenocarcinoma↗
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

[Purification of cytochrome P-450 and NADPH cytochrome p-450 reductase from human liver].

Two methods for the purification of cytochromes-P450 from microsomes of human liver are described. Method A: Cyt-P450 were solubilized from microsomes using a non ionic detergent, the Lubrol. The Cyt-P450 were purified by affinity, hydrophobicity followed by ion-exchange chromatography on DEAE-5PW column (HPLC) with an overall yield of 18% and a specific activity of 10 nmole/mg of protein. The recovery of NADPH Cyt-P450 reductase by method A (affinity) is about 60% with a specific activity of 16.2 U.I./mg of protein. Method B: Cyt-P450 were solubilized from microsomes using a zwitterionic detergent, the CHAPS. Cyt-P450 were filtered and separated by chromatofocusing on Mono-P column (HPLC). By this method it was possible to increase strongly the specific activity keeping a yield of 50% of Cyt-P450. Also it was possible to apply this method to small samples of human liver like biopsies (0.5 to 2.5 g).

Cytochrome P-450 Enzyme System↗
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

[Enrichment of cytochrome P-450 in human liver microsomes by the action of proteases].

Human liver microsomes have been partially enriched in cytochrome P450 using a simple and rapid method. Microsomes were digested with protease XXVII (40 micrograms/nmole cyt. P450), then incubated with CHAPS, a zwitterionic detergent (25 mg/nmole cyt. P450) in combination with 0.07% protamine sulfate and the solubilized cyt. P450 was separated by ultracentrifugation. By this method, about 35% of total microsomal protein was solubilized with more than 80% of cyt. P450. This technique increases the specific activity of cyt. P450 by three fold.

Cholic Acids↗
PubMedDate not supplied

Antitumor activity in the acridine series.

The antitumor effect against experimental tumors in mice of three acridine derivatives analog or homolog of N-[4'-(9-acridinylamino)-3'-methoxyphenyl]-methanesulfonamide has been investigated. The 3,6-bis-dimethylamino analog (DAMSA) showed important antitumor effect in murine leukemias and moderate effect in a solid tumor, the M5076 reticulosarcoma. The body weight loss of the treated mice was always within an acceptable range when 100 mg/kg were administered under the conditions of the experiment. However, a systemic toxic effect could be observed when 200 mg/kg were used. This preliminary data may be considered as an important step in the development of new acridine analogs with a different spectrum of antitumor activity.

Acridines↗
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

A new assay to evaluate cell growth and drug sensitivity in culture using a cell image processor.

The use of a cell image processor for the in vitro assessment of drug effects on cell growth, cell kinetics and chromatin organization is described. We have studied the influence of two well documented cytotoxic drugs, i.e. BCNU and vincristine (VIN), on the above mentioned parameters of the P-388 mouse leukemia, MCF-7 human mammary and HBL human melanoma cell lines. The cells were cultured for 1 to 4 days on glass coverslips put in Petri dishes containing or not (control) 10, 1 or 0.1 microgram/ml medium of the drug, after which they were fixed for histology, Feulgen-stained and analyzed through a cell image processor, i.e. the System for Analytical Microscopic Biomedical Applications (SAMBA 200). Our results showed that both BCNU and VIN exerted a well-known antineoplastic effect that was assessed at three different but highly complementary levels on the same sample of cells in a very rapid and simple procedure.

Animals↗
PubMedDate not supplied

Antitumour activity of a new water-soluble nitrosoureido sugar: CY233 (NSC 609224).

L1210 leukemia was used to evaluate the antitumour activity in vivo of CY233 (NSC 609224) a new water-soluble nitrosoureido derivative of deoxysugar currently being studied in preclinical trials. The antitumour activity of CY233 is dose-dependent with the same large therapeutic index whatever the route of administration (I.P., I.V., per os). Thus starting from a single dose of 10 mg/kg (less than 25% of the LD50), 80% to 100% of mice survive at 120 days, whether the drug is being administered I.V., I.P. or P.O. These results clearly emphasize the very original and promising potentiality of CY233 among the series of alkylating agents, and more precisely nitrosoureas.

Animals↗
PubMedDate not supplied

Phenotypic change of the transplantable MXT mammary adenocarcinoma into mixed bone producing sarcoma-like tumors.

The B6D2F1 mouse mammary adenocarcinoma was adapted to grow in vitro as monolayer. After in vitro passaging of tumor cells, phenotypic changes occurred that were expressed in vivo. Following intraperitoneal inoculation of tumor cells, bone-forming tumors developed. These tumors consisted of undifferentiated adenocarcinoma mixed with large amount of cartilagenous and osseous tissue. The etiology of these phenotypic changes was not yet determined. However, hypothesis of the possible origin of the cartilage and bone forming tissue was formulated. The biologic characterization of the intraperitoneally bone-forming tumor was achieved and the experimental conditions to preserve and induce the reproducible sarcoma-like bone forming tumors were defined. Our data support the usefulness of this new original model for fundamental research as well as for screening of anticancer drugs.

Adenocarcinoma↗
PubMedDate not supplied

Influence of inoculation sites and tumor cell culture techniques on the phenotype of a mixed cartilage- and bone-producing mouse mammary tumor.

We have previously reported the characterization of an intraperitoneally (IP) transplantable bone-forming MXT tumor. However, the question was unresolved as whether the bone-forming cells originated from either the host animal or from the neoplasm itself. The present work attempts to answer this question by studying the influences of inoculation sites (subcutaneously, SC; intraperitoneally, IP; in the brain, IB; intracranially, ICR) on both the cartilage- and bone-forming tumor phenotypes. Furthermore the influence of cell culture procedures (two- and three- dimensional cultures) on these phenotypes was investigated. SC administered MXT cancer cells never produce bone-forming tumors, suggesting the existence in the dermis of substance(s) inhibitory to the formation of cartilage or bone. On the contrary, our data clearly demonstrate that bone-forming tumors can be obtained by either IP route, in a way which mimics endochondral ossification, or in the brain (IB), a region usually devoid of connective tissue. This observation substantiates the hypothesis according to which the tumor itself is able to produce osseous tissue. Another main finding is the increasing occurrence of skeletal tissues produced by cells proceeding from three-dimensional culture. Finally, ICR and IB tumors exerted a bone-lytic action against the host skull suggesting that tumor cells either produce osteolytic substances (prostaglandins, enzymes) and/or that they contain various cell types exhibiting different properties toward osteogenesis. This model offers new perspectives for studying the mechanisms of both normal and pathologic osteogenesis.

Animals↗
PubMedDate not supplied

Effect of duration of exposure to S9788, cyclosporin A or verapamil on sensitivity of multidrug resistant cells to vincristine or doxorubicin.

In order to explain the high potency of S9788, a new multidrug resistance modifier currently in clinical development, we investigated its accumulation and retention in sensitive and resistant cells. Our results show that S9788 is 13-fold more accumulated and 23-fold more retained than VRP in the resistant S1/tMDR cell line. We also studied the effect of duration of incubation on the ability of S9788, verapamil and cyclosporin A to overcome the resistance of S1/tMDR and KB-A1 cells to a short exposure of doxorubicin or vincristine. Compared to a single co-incubation of 4 h, a 24 h post-incubation with 5 microM S9788 markedly increased the reversal of S1/tMDR resistance to VCR (fold reversal 4 h = 123; fold reversal 24 h = 4739), while it moderately increased S1/tMDR sensitivity to DOX (fold reversal 4 h = 1.9; fold reversal 24 h = 2.9). Similar results were obtained on KB-A1 resistance to VCR (fold reversal 4 h = 41, fold reversal 24 h = 21819) and KB-A1 resistance to DOX (fold reversal 4 h = 89; fold reversal 24 h = 160). This phenomenon also occurred with verapamil and cyclosporin A. These results clearly show that the effect of duration of exposure on the modulating activity of S9788 and of the 2 other modulators depends on the cytotoxic drug. Although the direct transposition of these results to a clinical situation is difficult, they suggest that a continuous infusion of S9788, starting simultaneously with the administration of the cytotoxic drug and ending 24 h later, might be a more effective schedule for clinical administration than a bolus administration.

Antineoplastic Agents↗