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Biomedical subjects

M Dufour

Publications and source records attributed to M Dufour.

At least 73 records · Page 4Linked to original sources
PubMed1986

In vitro comparative studies of the myelotoxicity and antitumor activity of 6-[bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose versus melphalan utilizing the CFU-C and HTSCA assays.

6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 microM, at which C-6 was significantly (P less than 0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 microM (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 microM for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 microM. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man. In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecule.

Analysis of Variance↗
PubMed1985

Effects of amino acids on the transport and cytotoxicity of melphalan by human bone marrow cells and human tumor cells.

In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture.

Adenocarcinoma↗
PubMed1985

Utilization of the HTSCA and CFU-C assay to identify two new 2-chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human glioma compared with BCNU.

AspCNU and SarCNU are two amino acid amide congeners (L-asparaginamide and sarcosinamide congeners) of chloroethylnitrosoureas. The in vitro myelotoxicity of these agents compared with BCNU at 1-8 micrograms/ml was determined in bone marrow cells from normal volunteers in the CFU-C assay. AspCNU and SarCNU were significantly (P less than 0.05) less myelotoxic than BCNU at equivalent microgram concentrations. SarCNU or AspCNU at 3 micrograms/ml demonstrate equivalent in vitro myelotoxicity to BCNU 1 microgram/ml. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained four specimens of malignant glioma and one specimen of meningioma from patients not previously treated with chemotherapy. AspCNU and SarCNU were significantly (P less than 0.05) more active than BCNU at 1-3 micrograms/ml concentrations in the HTSCA in all four malignant glioma specimens. In the one meningioma specimen, BCNU was significantly (P less than 0.05) more active than either AspCNU or SarCNU at all concentrations studied. These results suggest that AspCNU or SarCNU at doses that should produce less myelotoxicity than BCNU may be more active than BCNU against gliomas.

Antineoplastic Agents↗
PubMed1984

Effect of administration of sodium cyanate and melphalan on the lifespan of P388 tumor-bearing CD2F1 mice.

Sodium cyanate (NaOCN) at a dose of 250 mg/kg was shown to decrease protein synthesis in P388 leukemia tumor cells to approximately 52% of control values at 2 h and 32% at 5 h after NaOCN administration, without a corresponding decrease in various normal tissues of the tumor-bearing CD2Fl mice. CD2Fl mice that had received P388 tumor cells IP 1 day prior to drug administration underwent various schedules of treatment with NaOCN and melphalan (MLN). NaOCN (200 mg/kg or 250 mg/kg) administered IP has no significant antitumor activity (increased mean lifespan [ILS] less than 20%). The simultaneous IP administration of NaOCN (250 mg/kg) plus MLN (15 mg/kg) resulted in a significantly greater antitumor activity (approximately 265% of control, with 21 of 30 animals being long-term survivors) than MLN (15 mg/kg) alone (approximately 156% of control, with 11 of 30 animals being long-term survivors). This synergism was not observed when MLN was administered 4 h after NaOCN administration. The synergistic activity of MLN with NaOCN does not appear to be secondary to alterations in the absorption from the peritoneal cavity into the systemic circulation as determined by 3H2O. NaOCN does not increase the intracellular concentration of [chloroethyl-14C]MLN into P388 cells. The mechanism of the synergistic antitumor activity of simultaneous IP administration of NaOCN and MLN is unknown.

Absorption↗
PubMed1983

Comparison of the transport of chlorozotocin and CCNU in L1210 leukemia and murine bone marrow cells in vitro.

The uptake of radiolabeled CLZ and CCNU by L1210 leukemia and murine bone marrow cells was investigated to determine whether the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA of 1.3 by 0.1 mM CLZ, as against a ratio of 0.6 by equimolar CCNU, is secondary to differences in uptake. The concentration of intact CLZ was determined in the medium and the intracellular water space. The cell: medium ratio (intracellular concentration/medium concentration) of CLZ in bone marrow cells was greater than that seen for L1210 cells. However, the intracellular CLZ concentration generally remained constant in both cell types at 37 degrees C, between 7.0 and 10.0 pmole/microliters. The L1210: murine bone marrow cell ratio of intracellular CLZ concentrations was approximately 1.0 from 10 to 60 min. The intracellular CCNU concentration during the uptake of 0.1 mM (chloroethyl-U-14C) CCNU at 37 degrees C was constant at 85 pmol/microliters from 10 to 60 min in L1210 cells, but slowly decreased from 66 pmole/microliters at 20 min to 43 pmole/microliters at 60 min in bone marrow cells. The L1210: murine bone marrow cell ratio of intracellular CCNU concentrations ranged from 1.45 to 1.98 from 20 to 60 min. Thus, it appears that the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA by CLZ compared with equimolar CCNU cannot be explained by differences in uptake of the two agents by the two cell types. The uptake of 0.1 mM CLZ at 37 degrees C by L1210 cells in McCoy's 5A medium containing 300 mg% glucose was not affected by the addition of 5 mM cold drug, nor was it affected by the absence of glucose in the medium, with or without cold drug. This suggests that CLZ uptake into L1210 cells is via passive diffusion and that CLZ does not enter these cells via the glucose transport mechanism.

Animals↗
PubMed1981

Heterocyclic polycyclic aromatic hydrocarbon carcinogenesis: 7H-dibenzo[c,g]carbazole metabolism by microsomal enzymes from mouse and rat liver.

The metabolism of dibenzo[c,g]carbazole (DBC), was studied in vitro using microsomal fractions of mouse and rat liver from animals, which were treated with 3-methylcholanthrene (MC). The separation of extractable metabolites by high pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC) as well as identification of most of them by nuclear magnetic resonance, mass spectrometry and comparison with synthetically obtained products are described. The microsomes of both species produced the same twelve compounds of which the following have been identified: five monohydroxylated derivatives (phenols), the product of further oxidation of one of them, and a dihydrodiol. The 5-OH-DBC (60% including its spontaneously-formed dimer) and the 3-OH-DBC (14%) are the main metabolites. Three minor metabolites cochromatographed with synthetically prepared 2-OH-DBC, 4-OH-DBC and 6-OH-DBC. The dihydrodiol detectable in small quantity (4-6%) was tentatively identified as 3,4-dihydroxy-3,4-dihydro-DBC by the sensitivity of its formation to very low concentrations of the inhibitor of microsomal epoxide hydrolase, 1,1,1-trichloropropene oxide, by its molecular ion and major fragment in mass spectrometry and by its dehydration product 3-OH-DBC. No other dihydrodiols were detected. The qualitative and quantitative effects of various modulators of metabolism (enzyme inhibitors, apparently homogeneous epoxide hydrolase, glutathione, supernatant fraction) were investigated. The results are discussed with respect to possible ultimate carcinogens.

Animals↗
PubMed1979

Carcinogenicity and polarographic behaviour of dibenzo[a,h]pyrene, 4,11-diazadibenzo[a,h]pyrene and 7,14-diazadibenzo[a,h]pyrene.

In a simultaneous test of carcinogenicity the writers have studied the activities of dibenzo[a,h]pyrene (I), 4,11-diazadibenzo[a,h]pyrene (II) and 7,14-diazadibenzo[a,h]pyrene (III). These compounds were dispersed in paraffin disks and subcutaneously implanted in rats. Each experimental group consisted of 30 animals. The number of sarcomas induced by (I) and (II) was 23 and 16 respectively. The compound (III) has proved wholly inactive. Tumorigenicity of (I) and (II) was found to be proportional to their electron donation and inversely proportional to their electron acceptance in the performed polarographic test. Inactivity of (III) is being discussed from the aspect of molecular geometry.

Animals↗