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Biomedical subjects

G Atassi

Publications and source records attributed to G Atassi.

At least 127 records · Page 7Linked to original sources
PubMed1984

Preclinical studies on toxicity, antitumour activity and pharmacokinetics of cisplatin and three recently developed derivatives.

Preclinical studies were performed in mice, rats and dogs of cis-diamminedichloroplatinum(II) (CDDP) and its derivatives cis-1,1-di(aminomethyl) cyclohexane platinum(II) sulphate (TNO-6), cis-diammine-1,1-cyclobutanedicarboxylate platinum(II) (CBDCA) and cis-dichloro, trans-dihydroxybis-isopropylamine platinum(IV) (CHIP). In mice toxicity and antitumour activity were determined. All three derivatives were at least as toxic as CDDP for haemopoietic stem cells and were less active than CDDP against the mouse tumours leukaemia L1210 and osteosarcoma C22LR. Toxicology studies in rats revealed no renal toxicity after a single dose of TNO-6. Fractionated doses of TNO-6 and CBDCA did cause renal toxicity but less than CDDP. CHIP produced little or no kidney damage. In dogs, TNO-6 (1.5 mg/kg) produced more severe kidney damage--although this was reversible--than CDDP (2 mg/kg). Half-lives of distribution were 4.0-5.1 min for TNO-6 and 9.7 min for CDDP, while half-lives of elimination were 3.6-6.6 days and 5.9 days respectively. Plasma levels, normalized for the dose, were at least two times higher after TNO-6 than after CDDP. Twelve weeks after drug administration, plasma levels were undetectable, while tissue concentrations could still be measured. The platinum concentration in kidney cortex was higher after CDDP than after TNO-6.

Animals↗
PubMed1984

Characterization of the activity of alpha/beta-triglycidylurazol (TGU; NSC-332488): a new antineoplastic compound.

The antitumour properties of alpha/beta-triglycidylurazol (TGU) were investigated on various transplantable mouse tumour systems. A high rate of cures of P388 and L1210 leukaemias was obtained with this compound. TGU also had an antitumour effect against B16 melanoma, the colon 38 tumour and the advanced RC renal carcinoma, producing a total regression of the tumour. Finally, the marked in vivo activity of TGU against a subline of P388 leukaemia totally resistant to cyclophosphamide (CP), its good water-solubility (7%) and its stability in neutral pH are further elements warranting clinical studies with this agent.

Animals↗
PubMed1984

Preclinical evaluation of the anti tumour activity of new epoxyde derivatives.

As a follow-up to our initial results on the antineoplastic activity of alpha-1,3,5-triglycidyl-s-triazinetrione (alpha TGT, NSC-296934, Teroxirone), many new epoxyde derivatives were tested against murine tumours, mostly against P388 leukaemia, to determine their antineoplastic role and to characterize their specific effect against tumour cells in vivo, as well as to select an analogue with higher anti-cancer properties and superior pharmacological properties. Triglycidyl urazol (TGU, NSC-332488) showed the highest therapeutic activity and a good level of water-solubility which makes this agent a good candidate for phase-one clinical trials.

Animals↗
PubMed1984

Investigation of the antitumor activity of new epoxide derivatives. Part II: N-glycidylated oxo-nitrogen heterocycles.

A number of N-glycidyl compounds derived from oxo-substituted nitrogen heterocycles such as diazines, triazines, diazoles, triazoles as well as condensed ring systems containing these units have been synthesised. All products were tested for their antitumor activity against leukaemia in the mouse. Almost all of the approx. 50 di- and triglycidyl compounds showed activity, whereby 5 of them exhibited an increase of lifespan of 200% and more. The most active compound was 1,2,4-triglycidyl-urazol.

Animals↗
PubMed1984

In vitro assessment of cytotoxic agents in murine cancers: comparison between antiproliferative and antimetabolic assays.

Different methods were compared for the in vitro evaluation of the therapeutic effects of the antineoplastic agents doxorubicin, cisplatin, fluorouracil, and vinblastine sulfate in a model system of murine tumor cell lines consisting of L1210 leukemia, P815 mast cell leukemia, and B16 melanoma. Excellent correlations were found with the in vivo effects with the use of a soft agar clonogenic assay, irrespective of the method of growth assessment (i.e., visual colony counting or incorporation of tritiated thymidine in proliferating colonies). Drug effects on the proliferation of tumor cell lines in liquid medium frequently led to an overestimation or underestimation of the actual in vivo effects. Direct incorporation of the radiolabeled precursors thymidine, uridine, and leucine after pretreatment with drugs always led to the prediction of resistance and was therefore considered unreliable.

Animals↗
PubMed1984

Growth response of B16 melanoma to in vivo treatment with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) at the initial stage after tumor transplantation.

The changes of implanted B16 melanoma fragments in situ following early treatment with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) were studied by quantitative histopathologic methods from Day 1 to Day 7 and at Day 14 after transplantation. During the first 3-day period there were no apparent differences between the two groups in all the parameters studied. The most striking differences were observed on Day 5 after implantation, when the drug-treated tumor showed the lowest number of morphologically intact tumor cells and the lowest level of proliferative capacity, with a high proportion of melanotic cells. The late infiltration of host macrophages was more abundant in drug-treated tumors than in controls due to an enhanced production and liberation of melanin granules. The results suggest that a 7-day growth delay of drug-treated tumors is characterized not only by a reduced number (one order of magnitude) of intact tumor cells but also by a severely suppressed proliferative capacity.

Animals↗
PubMed1983

Development and characterization of a new murine renal tumor model. Chemotherapeutic results.

A murine renal cell carcinoma model, the RC tumor, was pharmacologically and histologically characterized and was used for the evaluation of 20 chemotherapeutic agents. This model, when implanted IP or SC showed reproducible behavior and was found to be very sensitive to many drugs with different mechanisms of action, and particularly to alkylating agents. The IP-implanted tumor was sensitive to some clinically active drugs which were reported inactive against L1210 or P388 murine leukemias. The highest sensitivity of this model than of L1210 and P388 leukemias makes the RC tumor a good prescreening system for testing potential chemotherapeutic agents.

Adenocarcinoma↗
PubMed1983

1,3-dipalmitoylglycerol ester of chlorambucil as a lymphotropic, orally administrable antineoplastic agent.

A glyceride derivative of chlorambucil (2), 1,3-dipalmitoyl-2-[4-[bis (2-chloroethyl)amino]benzenebutanoyl]glycerol (1), was synthesized and tested as an orally administrable antineoplastic drug endowed with lymphotropic properties. A significantly higher efficacy (increased life span) and a reduced toxicity of 1, relative to 2, were apparent when both compounds given per os were evaluated against P388 leukemia subcutaneously implanted in mice, a situation where the tumor cells disseminate along the lymphatic route. In order to assess the selective absorption of 1 by the intestinal lymphatic system after oral administration, we determined plasma and intestinal lymphatic concentrations and compared them with that obtained with 2. The results clearly demonstrate that the esterification of 2 to a diacylglycerol moiety brings about considerably higher levels in the lymph and reduces plasma levels. Moreover, pharmacokinetic and biological data suggest that 1 is most probably acting by itself rather than as a prodrug of chlorambucil.

Administration, Oral↗
PubMed1983

Chemotherapeutic efficacy of Nocodazole encapsulated in liposomes on L1210 murine leukemia.

The use of sonicated phospholipid vesicles (liposomes) as carriers of methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl] carbamate (Nocodazole), a water insoluble antimitotic compound active on mouse L1210 leukemia was investigated. Nocodazole was incorporated in dipalmitoyl-phosphatidylcholine: cholesterol: stearylamine (4:3:1) liposomes that were stable at room temperature for at least 48 hr. No drug leakage nor lipid exchange occurred after a 4 hr incubation at 37 degrees C with RPMI 1640 medium supplemented with 10% fetal calf serum. L1210 cells preincubated (2 x 10(6) cells/ml) at 37 degrees C for 3 hr with various concentrations of micronized Nocodazole or liposome-entrapped Nocodazole were injected i.p. into normal CDF1 mice (10(5) cells/mouse). Longest mean survival times and long-time survivors were observed in the group inoculated with L1210 cells preincubated with liposomes containing Nocodazole. CDF1 mice bearing i.p. or i.v. L1210 leukemia were treated i.p. on days 1, 5 and 9 with micronized or liposome-entrapped Nocodazole. Administration of this latter preparation induced a 50% increase in animal life span at the dosage (25 mg/kg/day) half the one required with the free compound (50 mg/kg/day). The present data indicate that enclosing Nocodazole, a water insoluble antimitotic compound, in liposomes results in an enhanced therapeutic activity against L1210 murine leukemia.

Animals↗
PubMed1983

Iv administration of a water-insoluble antimitotic compound entrapped in liposomes. Preliminary report on infusion of large volumes of liposomes to man.

Five patients with advanced multiresistant neoplasms were infused with NSC-251635 (a water-insoluble antimitotic agent) entrapped in egg yolk lecithin, cholesterol, and stearylamine liposomes. The maximum volume injected was 400 ml containing 8 g of lipids, ie, a dose of 135 mg/kg of body weight. Overall tolerance of the treatment was excellent. This study indicates that liposomes may be used safely as carriers for the iv administration of water-insoluble drugs to humans.

Adenocarcinoma↗
PubMed1983

Antitumor activity of a water-insoluble compound entrapped in liposomes on L1210 leukemia in mice.

The use of sonicated phospholipid vesicles (liposomes) as carriers of 2-[3'-(methoxycarbonylamino)-phenyl]-3-phenyl-6-methoxycarbonylamino-4-(3H)- quinazolone (NSC-251635), a water-insoluble antimitotic compound, was investigated in mice. NSC-251635 was incorporated in egg yolk lecithin, cholesterol, and stearylamine (4:3:1) liposomes. In vitro, NSC-251635 in suspension or entrapped in liposomes was not toxic for L1210 cells. In vivo, after ip or iv injections to CDF1 mice bearing intraperitoneal or intravenous L1210 leukemia, NSC-251635 was active only when it was incorporated in the liposomes and not when it was given as a suspension in Klucel or in saline. The NSC-251635 liposome preparation induced significantly prolonged survival of the treated animals.

Animals↗
PubMed1982

Degree of differentiation and blood vessel proximity in B16 melanoma.

Corded structures consisting of rows of viable tumour cells around a central blood vessel are present in a number of transplantable mouse tumours, including transplantable B16 melanomas. These tumours were used to assess, by stereological means at the EM level, the range of differentiation of the melanoma cells, according to their position in relation to the central blood vessel. The mitotic index was also determined for perivascular and peripheral tumour cells separately. Furthermore, the transition of peripherally located cells into necrotic tumour cells is described at the EM level. Results shown an important increase in differentiation in peripheral tumour cells, whereas the mitotic index is highest in perivascular cells. Necrotic peripheral cells show features of apoptotic necrosis, together with necrosis of the ischaemic type. Results indicate that both proliferation and differentiation of melanoma cells are related to their position around a central blood vessel, and that peripheral necrosis is not exclusively due to lack of oxygen.

Animals↗
PubMed1982

N-methylformamide: antitumour activity and metabolism in mice.

The antitumour activities of N-methylformamide, N-ethylformamide and formamide against a number of murine tumours in vivo (Sarcoma 180, M5076 ovarian sarcoma and TLX5 lymphoma) have been estimated. In all cases N-methyl-formamide had significant activity, formamide had marginal or no activity and N-ethylformamide had no significant activity. N-methylformamide and N-ethylformamide were equitoxic to the TLX5 lymphoma in vitro. Formamide was found as a metabolite in the plasma and urine of animals given N-methylformamide and N-ethylformamide, but excretion profiles do not support the hypothesis that formamide is an active antitumour species formed from N-alkylformamides. No appreciable metabolism of N-methylformamide occurred under a variety of conditions with liver preparations in vitro. N-methylformamide, but not N-ethylformamide or formamide, reduced liver soluble non-protein thiols by 59.8% 1 h after administration of an effective antitumour dose.

Animals↗
PubMed1982

Investigation of the in vivo anti-invasive and anti-metastatic effect of desacetyl vinblastine amide sulphate or vindesine.

In a study of the effect of vindesine (VDS) against metastases of murine tumours in vivo, we demonstrated that VDS produced an anti-metastatic effect on tumours with invasive properties, such as Lewis lung carcinoma or Madison 109 lung carcinoma, while no effect was observed against lymph node metastases of the subcutaneously implanted P388 tumour model. Local systemic mechanisms favouring or opposing the phenomena of invasion, dissemination, and establishment of secondary malignancies may explain the differences between the various models. Although our data did not allow us to conclude that VDS has specific anti-invasive properties in vivo, its inhibitory effect against secondary tumour growth agrees with the assumption that invasion is an important step in the establishment of metastases.

Animals↗