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Biomedical subjects

G Atassi

Publications and source records attributed to G Atassi.

At least 91 records · Page 5Linked to original sources
PubMed1992

In vitro and in vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative.

S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5 microM) was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5 microM). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50-100 mg/kg/d) administered IP once a day on days 1-4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR - bearing mice and ADR (4 mg/kg/d) in P388/ADR - bearing mice. Increases in antitumor activity were (% T/C) of +20-34% in the P388/ADR model and + 50-78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5-10 microM) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDR in vitro and in vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.

Animals↗
PubMed1991

N-myristoyl-transferase activity in cancer cells. Solubilization, specificity and enzymatic inhibition of a N-myristoyl transferase from L1210 microsomes.

The activity catalyzed by N-myristoyl transferase (NMT) is described for the first time in microsome-rich fractions from the murine leukemia cell line L1210, rat brain and mouse liver as biological sources. The enzyme from each source can accommodate various types of proteins (protein kinase A, virus structural gag protein or pp60src) as modelized by the use of their N-terminal derived peptides (GNAAAARR, GQTVTTPL and GSSKSKPKDP, respectively). As for some other types of membrane-bound enzymes, NMT activity can be enhanced by pretreatment with various types of detergents, amongst which Triton 770 and deoxycholate were the most potent. Further experiments on the L1210 microsome-rich fractions demonstrate that these two detergents were able to solubilize the microsomal enzyme, without modifying its substrate specificity. Finally, three compounds described in the literature to be inhibitors of NMT activity from other sources were tested for L1210 microsome-associated activity. None of them show any significant potency in inhibiting this activity. A new compound, myristoylphenylalanine, shows a slightly better inhibitory effect on the L1210 microsomal activity than the reference compounds with a median inhibitory concentration (IC50) of 0.2 mM.

Acyltransferases↗
PubMed1991

Preclinical antitumor activity of a new Vinca alkaloid derivative, S 12363.

S 12363 is a new Vinca alkaloid derivative obtained by appending an optically active alpha-aminophosphonate at the C23 position of O4-deacetyl vinblastine. S 12363 was evaluated for cytotoxic and antitumor activity against a spectrum of murine and human tumors. This compound was, respectively, on average, 72- and 36-fold more cytotoxic than were vincristine and vinblastine, when tested on a panel of 2 murine and 37 human tumor cell lines using the microculture tetrazolium assay. S 12363 exhibited significant antitumor activity against murine transplantable tumors (i.p. and s.c. P388 leukemia, i.p. L1210 leukemia, i.p. and i.v. B16 melanoma, i.p. M5076 sarcoma, and s.c. colon adenocarcinoma 38), while no activity was observed on s.c. Lewis lung carcinoma. S 12363, when administered i.p., showed moderate activity on human NCI-H460 lung and PANC-1 pancreas tumor xenografts in nude mice. However, when it was administered i.v., it exerted a significant activity against human HT-29 colon, NCI-H460 lung, NCI-H125 lung, PANC-1 pancreas, and A-431 vulvar tumor xenografts. S 12363 was also active in vivo against a P388 leukemia subline resistant to vincristine. On the in vivo panel of tumors used in this study, S 12363 was at least as active as reference compounds, while its optimal dosage was 10- to 40-fold lower than that of vinblastine, depending on the models studied. The effects of schedule and route of administration on the antitumor activity of S 12363 were studied in both i.p. inoculated P388 leukemia and B16 melanoma, in which the activity was improved by single and intermittent treatment (Days 1, 8, and 15) and i.p. route. S 12363, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 300-fold less cytotoxic and 1000-fold less potent in vivo than was S 12363. These results suggest that S 12363 could present a therapeutic advantage over its congeners and deserves further pharmacological evaluations.

Animals↗
PubMed1991

Chemical stability of ecomustine, a new antitumor agent in aqueous and biological media as assessed by high-performance liquid chromatography.

Ecomustine, or CY233 (NSC-609224), is a new water-soluble nitrosoureido sugar derived from acosamine. A high-performance liquid chromatographic assay (HPLC) developed to quantify the unchanged drug in aqueous solutions and biological specimens enabled us to study the chemical stability as a function of pH, light, and temperature. In buffered aqueous solutions, the kinetics of degradation of CY233 is a first-order process. The log k-pH profile demonstrated hydroxide ion-catalyzed solvolysis. The drug is most stable at pH 4, more stable than some other nitrosoureas in 5% glucose (t1/2, 62-67 h) and in 0.9% isotonic saline (t1/2, 25-37 h) solutions. Based on these findings, blood samples should be collected in cold tubes (4 degrees C) containing citrate buffer (pH 4) and all manipulations should be protected from heat and light.

Antineoplastic Agents↗
PubMed1991

The antitumor activity and the structure of bis(adeninato-N9) diphenyltin(IV).

Bis(adeninato-N9)diphenyltin(IV) has been selected as a tumor panel compound by the U.S. National Cancer Institute and tested against a number of tumors according to standard protocols. The activity criteria were not passed. The solid state structure of the environment of tin in the complex has been definitely established to be of the tetrahedral type by means of 119Sn Mössbauer-Zeeman spectroscopy; this configuration has been assumed to be maintained also in aqueous suspensions of the drug, in conditions corresponding to the administration to mice. The occurrence of strong Sn-N bonds, consistently resistant to hydrolytic processes, has been assumed, and correlated to the observed low toxicity of the drug. The extent of the antitumor action corresponds to the standard response to Ph2SnIV moieties.

Adenine↗
PubMed1991

Antitumor activity of quassinoids from Hannoa klaineana.

Of the five quassinoids isolated from the root bark of Hannoa klaineana, only 15-desacetylundulatone was found active against P388 mouse lymphocytic leukemia cells and colon 38 adenocarcinoma. Undulatone and especially 15-O-beta-D-glucopyranosyl-21-hydroxy-glaucarubolone were found to be more toxic while 6 alpha-tigloyloxy-glaucarubol and 21-hydroxyglaucarubolone were found inactive. Structure-activity relationships are discussed.

Adenocarcinoma↗
PubMed1991

Heterocyclic quinones. 17. A new in vivo active antineoplastic drug: 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione.

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.

Animals↗
PubMed1991

[Farnesyltransferase as target for non-cytotoxic anti-cancer agents: first steps].

Farnesylation is a key maturation step involved in the ras-dependent transformation of cells. This acylation step is catalyzed by protein: farnesyltransferase, a soluble enzyme. The present work describes the use of a new HPLC method of measurement of this enzymatic activity using the K-ras-derived CVIM tetrapeptide as substrate. The method is used to check the activity catalyzed by cytosols issued from various types of cancer cells. J82, a human bladder cancer cell line was retained for measurement of the inhibitory potency of a few peptide sequences and will be used as starting biological material for the purification of the enzyme. This HPLC method presented herein has the main advantages over other published methods of being automatisable and versatile, because it can be used with a wide spectrum of peptide substrates. Results presented herein are only first studies and need some more structural observations. The obtention of the cancer cell line-derived, partially purified farnesyltransferase will hopefully lead us to the discovery of specific inhibitors with potential non-cytotoxic anti-cancer activities.

Animals↗
PubMed1989

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-compl exe s, Part I: Synthesis.

The synthesis of the stereoisomeric 1,2-bis(3-hydroxyphenyl)ethylenediamines (1-4) from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3-methoxybenzaldehyde by a diaza-Cope-rearrangement and subsequent ether cleavage with BBr3 and their conversion into the [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-complexes with K2PtCl4 (1-PtCl2 - 4-PtCl2) is described.

Antineoplastic Agents↗
PubMed1989

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl) ethylenediamine]dichloroplatinum(II)-complexes, Part II: Biological properties.

The activity of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine] dichloroplatinum(II)-complexes (1-PtCl2,R,S; 2-PtCl2, R,R/S,S; 3-PtCl2, R,R; 4-PtCl2, S,S) on several tumor models (MDA-MB 231 breast cancer cell line; P 388 leukemia, mouse; L 1210 leukemia, mouse; L 5222 leukemia, rat; Ehrlich ascites tumor, mouse--wildtype; cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.) is described. For comparison the analogous [1,2-bis(4-hydroxyphenyl)ethylendiamine]dichloroplatinum (II)-complexes (5-PtCl2, R, S; 6-PtCl2, R,R/S,S; 7-PtCl2, R,R; 8-PtCl2, S,S) and cisplatin are used. 1-PtCl2 to 4-PtCl2 (OH in 3,3'-positions) show their maximum antitumor effect at lower doses than 5-PtCl2 to 8-PtCl2 (OH in 4,4'-positions). 2-PtCl2 and 6-PtCl2 (R,R/S,S) are more active than 1-PtCl2 and 5-PtCl2 (R,S). 4-PtCl2 and 8-PtCl2 (S,S) are superior to 3-PtCl2 and 7-PtCl2 (R,R). On the L 5222 leukemia 2-PtCl2 (R,R/S,S), 4-PtCl2 (S,S) and 8-PtCl2 (S,S) markedly surpass cisplatin. Strong effects are produced by 2-PtCl2 to 4-PtCl2 on the Ehrlich ascites tumor (wildtype, cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.). The combination of 4-PtCl2 with cisplatin results in a weakly synergistic effect.

Animals↗
PubMed1989

Characterization of the anti-tumour activity against solid tumours of a new nitrosoureido sugar: Cy 233.

The anti-tumour properties of Cy 233, a new nitrosoureido sugar, were investigated in two murine solid tumours: B16 melanoma and subcutaneously implanted colon adenocarcinoma. Injected i.v., Cy 233 exerted a strong anti-tumour effect against the established B16 melanoma: long-term survivors were recorded with all schedules of treatment. The drug was even more effective against advanced colon 38 adenocarcinoma: it produced a high percentage of total tumour regression, regardless of the route of administration (i.p., i.v., p.o.). The marked in vivo activity of Cy 233 against advanced colon 38 adenocarcinoma, which is known to be resistant to such major anti-cancer drugs as BCNU and chlorozotocin, its water solubility and its stability in aqueous media are further elements warranting toxicological and clinical studies of this agent.

Adenocarcinoma↗
PubMed1989

Rationale for the synthesis and preliminary biological evaluation of highly active new antitumor nitrosoureido sugars.

Various new nitrosoureido derivatives of di- or trideoxy sugars were synthesized. The influence of the hydroxyl substitution pattern, the configuration at the anomeric center, and the absolute configuration of the sugar moiety on the antitumor activity of a series of nitrosoureido derivatives of di- and trideoxy sugars was studied. All compounds showed a very significant activity in vivo against L1210 leukemia, B16 melanocarcinoma, and Lewis lung carcinoma. Methyl 3-[3-(2-chloroethyl)-3-nitrosoureido]-2,3-dideoxy-alpha-D-arabino- hexopyranoside, 24 (NSC 609224), was found to be the most active compound. When treated with 24 (NSC 609224) at 20 mg/kg on day 1, at least 90% of the L1210 leukemia and B16 melanocarcinoma bearing mice showed a survival of over 60 days for a LD50 value for this compound of 42 mg/kg.

Amino Sugars↗
PubMed1989

Human medullary thyroid carcinoma: cell cultures and xenotransplants in nude mice. Immunocytochemistry and calcitonin secretion.

Occult primary and recurrent medullary thyroid carcinomas (MTC) detected only by elevated calcitonin levels in the peripheral blood, generally after pentagastrin-test stimulation, are difficult to localize. Some new imaging procedures with radionuclide tracers or radiolabelled monoclonal antibodies against carcinoembryonic antigen seem to bring some potentially therapeutic benefits. We report our results with cell cultures and xenotransplants of human MTC with the intention of establishing reproducible models in vitro and in vivo. Cell cultures secrete calcitonin at up to 1200 pg/ml for periods ranging from 3 to 13 weeks. Immunocytochemistry detects cytoplasmic granules positive for calcitonin in polygonal epithelioid cells with dendritic processes. Xenotransplants in nude mice fare better in the subcutaneous axilla than in the subrenal capsule assay. In the former location the tumor-take is good and calcitonin is detected in the blood of the tumor-bearing animals, at levels ranging from 286 to more than 20,000 pg/ml. These models would be potentially usable as targets for radionuclide tracers and/or radiolabelled monoclonal antibodies.

Animals↗
PubMed1989

Nucleoside analogues: 8. Some isomers of B.3839, the original 5-fluorouracil/nitrosourea molecular combination, and their effect on colon, breast and lung tumours in mice.

This study describes the manipulation of secondary products arising from the synthesis of the prototypical molecular combination of 5-fluorouracil (5-FU) and chloroethylnitrosourea (CNU), B.3839, in order to investigate the effects produced by connecting the C-S-C-C-CNU chain to the 5-FU ring in different ways. The isolation of phthalimide precursors of these compounds and the transformation into CNUs is described. Anti-tumour activity of these molecular combinations against a series of experimental murine colon, lung and mammary tumours is presented. The spectrum of anti-tumour activity displayed is interesting but defies simple explanation without further detailed in vivo pharmacokinetic and metabolism studies in order to define optimal profiles for activity.

Adenocarcinoma↗
PubMed1989

Nucleoside analogues. 9. Seco-nucleoside analogues of some 5-fluorouracil/nitrosourea molecular combinations having uracil as base: synthesis and anti-tumour activity.

The synthesis of representative seco-nucleoside analogues of 5-fluorouracil (5-FU)/nitrosourea molecular combinations having uracil (U) as base instead of 5-FU is described. The anti-tumour activity of corresponding pairs of drugs is compared in experimental tumours of the mouse colon, lung and breast. These studies have demonstrated that the presence of a hydrogen or fluorine atom at pyrimidine C-5 is unimportant for the activity shown against most of the experimental tumours employed, rather that the pyrimidine cyclic urea and/or alkylthio functionalities may constitute the critical factors. One exception is the prototypical compound B.3839 and its U analogue B.3912. B.3839 is highly active against colon 38 adenocarcinoma, a tumour which is highly responsive to 5-FU, whereas most of the activity is lost in B.3912. The 5-FU release profile of some of these molecular combinations could be adequate or effective in treatment of slow-growing clinical tumours.

Adenocarcinoma↗
PubMed1989

Nucleoside analogues: 7. Effect on colon, breast and lung tumours in mice of 5-fluorouracil/nitrosourea molecular combinations incorporating alkoxy and oxidized sulphur functions.

This study considers further changes in the carrier moiety of molecular combinations of the pyrimidine antimetabolite 5-fluorouracil (5-FU) and the alkylating group chloroethylnitrosourea (CNU). Detailed chemical syntheses are described of compounds incorporating (a) a simpler alkoxy group in the 'sugar' fragment, (b) attachment of the 5-FU residue to the C-X-C-C chain on the side of the heteroatom X distal from the CNU group, and (c) higher oxidation states of the sulphur atom in the prototypical compound B.3839. Anti-tumour activity of these analogues against a series of experimental murine colon, lung and mammary tumours is described. The pattern of activity reveals that the carrier moiety is important but further pharmacokinetics and metabolism studies are required to determine structure-activity relationships.

Adenocarcinoma↗
PubMed1988

Intraperitoneal chemotherapy with cisplatin and melphalan.

Cisplatin and melphalan given ip exert a synergistic therapeutic effect against ascitic P388 leukemia in mice and have different dose-limiting toxic effects as well as favorable pharmacokinetic characteristics in ip phase I studies. We gave a total of 98 courses of cisplatin (escalated from 40 to 120 mg/m2) and melphalan (escalated from 12 to 30 mg/m2) to 30 patients with ip tumors, most of whom had residual ovarian cancer following iv cisplatin-containing regimens. Treatment was delivered in 2 L of 0.9% NaCl through a Tenckhoff catheter with or without a Port-a-Cath system every 28 days for one to nine cycles. Myelosuppression was dose-related and leukopenia was dose-limiting. The maximum tolerated dose was 120 mg of cisplatin/m2 and 20 mg of melphalan/m2. With the exception of treatment-induced nausea and vomiting, nonhematologic toxic effects were mild and no (or very little) local toxicity occurred. Pharmacokinetic analyses showed that the areas under the peritoneal concentration versus time curve averaged 16-fold and 17-fold more than the area under the plasma curve for cisplatin and melphalan, respectively. Objective responses were documented by third-look laparotomy in ovarian cancer patients with minimal (less than 2 cm) residual disease.

Adult↗