Georges Soula

Serum apolipoproteins A-I, A-II and B in hepatic metastases. Comparison with other liver diseases: hepatomas and cirrhosis

Serum concentrations of lipids and apolipoprotein A-I, A-II and B were determined in patients with hepatic metastases of colorectal cancer, with primary liver cancer and with cirrhosis. In all three liver diseases, the HDL fraction and apolipoproteins A-I and A-II showed significantly low values, while apolipoprotein B was only increased in hepatic metastases. The decrease of apolipoprotein A-II levels was more prominent in cirrhosis, thereby enhancing the A-I/A-II ratio. This ratio is decreased in metastasis and normal in hepatomas. In patients with hepatic metastases a correlation was observed between alkaline phosphatase and apolipoprotein A-II (p less than 0.05), and between gamma-glutamyltransferase and the A-I/A-II ratio (p less than 0.05). The present work suggests that determination of apolipoproteins and lipids of the HDL fraction offers a new approach to the study of liver diseases.

Preparation of low density lipoprotein-9-methoxy-ellipticin complex and its cytotoxic effect against L1210 and P 388 leukemic cells in vitro

Previous studies have suggested that low density lipoprotein (LDL) may be used as a drug targeting carrier for chemotherapeutic agents to neoplastic cells. In this study the cytotoxic agent 9-methoxy-ellipticin (MeOE) was incorporated into dimirystoyl phosphatidylcholine, cholesteryl oleate stabilized microemulsion and the latter fused with human LDL. Both agarose electrophoresis migration and the electron microscopic shape of the drug-LDL complexes were similar to those of native LDL. The in vitro cytotoxic tests on L1210 and P388 leukemic cells demonstrated that the complex was able to kill cells and was more effective than the free drug. This cytotoxic activity of the drug-LDL complex depends on the LDL high affinity receptor: the native LDL reduces the killing power. In contrast, methylated LDL, which does not bind to the LDL receptor, has no effect on it. On the other hand, heparin, which prevents binding on the cell surface receptors, partially reduced the cytotoxic activity of the drug-lipoprotein complex. These results suggest that it is possible to incorporate lipophilic cytotoxic drugs into LDL, using a technique of fusion with the microemulsion which contains the drug. This technique allows us to obtain a drug-LDL complex which is able to kill cells via the LDL receptor pathway.

Quantitative Abnormalities of Lipoprotein Particles in Multiple Myeloma

Serum concentrations of total cholesterol and lipoprotein cholesterol, of apolipoproteins A I and A II and of apolipoprotein A I in lipoprotein particles (Lp A I and Lp A) were determined in 43 patients with multiple myeloma. There were striking alterations in the plasma levels of these analytes relative to normal subjects. We observed a decrease of cholesterol levels in LDL, HDL and HDL3 fractions, and of apolipoproteins A I and A II compared with normal subjects. The HDL2 cholesterol was increased. The decrease of apolipoprotein A II was more prominent than apolipoprotein A I. The decrease of apolipoprotein A I concerns only the A I (Lp A), while the A I (Lp A I) was increased. Most of these modifications were correlated with the monoclonal Ig levels.

Pharmacokinetics of Ro 03-8799 in mice bearing melanosarcoma: Comparison with tumors without melanin

The pharmacokinetics of Ro 03-8799 has been studied in melanic and non-melanic tumor bearing mice after iv administration of 150 mg/kg. The peak concentration in B16 melanosarcoma tumor reached 152 micrograms/g, that is 7.6-fold higher than the plasma concentration at the same time. This concentration is 3-times greater than that obtained in the tumor of mice bearing non melanic sarcoma (DB16) or Lewis lung carcinoma (3LL). The exposure of B16 tumor (AUC) is respectively 15-times and 11-times higher than the 3LL and the DB16 ones. These experimental data confirm that this 2-nitro-imidazol compound has an important affinity for melanin and suggest that it might be used as a radiosensitizer for the treatment of malignant melanoma.

Proliferative effect of high density lipoprotein (HDL) and HDL fractions (HDL1,2) HDL3/on virus transformed lymphoblastoid cells

The growth-promoting activities of plasma lipoproteins (LDL, HDL, HDL1,2, HDL3) and total HDL apolipoproteins on a virus transformed lymphoblastoid cell line in vitro, has been compared. When maintained in lipoprotein-deficient serum-supplemented medium, these cells do not proliferate optimally. The addition of either HDL, HDL1,2 or HDL3 induced optimal cell proliferation as compared to the result observed in fetal calf serum-supplemented medium. The HDL1,2 subfraction was found to be more potent than the HDL3 subfraction in supporting cell growth. Total HDL apolipoproteins were able to support significant cell proliferation. In contrast, LDL did not promote cell growth. In serum-free conditions and in the presence of transferrin, only HDL and HDL subfractions induced cell proliferation. These results suggest that HDL and HDL subfractions could initiate B lymphoblastoid cell growth and that total HDL apolipoproteins could support a part of cell proliferation.

Distribution and tumor penetration properties of a radiosensitizer 2-[14C] misonidazole (Ro 07-0582), in mice and rats as studied by whole-body autoradiography

SummaryThe hypoxic cell radiosensitizer 2-[14C] misonidazole: 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol (Ro 07-0582) MISO was administered to mice, control rats, and rats bearing chemically induced rhadbdomyosarcoma. The dose injected was 250 mg/kg and the delivered activity was 100 μCi/kg. Whole-body autoradiography was performed in all animals. We noted the highest uptake of radioactivity in the liver and the kidney. In the liver there was an accumulation of [14C] from 5 min to the 2 hour after treatment, followed by a decrease; this observation is probably related to the metabolic pathway of the drug. The radioactivity was also concentrated in the renal medulla (30 min after injection); this organ is the excretion route for most of the misonidazole or its metabolites. Fecal excretion is also important following biliary elimination. Radioactivity is present in the central nervous system in the first hours after dosage. [14C] Tumor activity was lowest 5 min after IP treatment. By contrast, 12 h after administration of labeled compound the highest activity was detected in this tissue.

Pharmacokinetics of teniposide (VM 26) after IV administration in serum and malignant ascites of patients with ovarian carcinoma

SummaryNine patients with ovarian carcinoma and malignant ascites treated with IV teniposide chemotherapy (30 mg/m2/30 min) entered this study. Plasma and peritoneal fluid levels were measured by an HPLC method with electrochemical detection. Plasma decay kinetics followed a triexponential function. A high variability of drug diffusion in ascites was noticed. Peak concentrations in ascites ranged from 1.6% to 20.5% of serum peak concentration. The concentration in peritoneal fluid reached a maximum level 6 h after the infusion ended. Teniposide was less slowly eliminated from ascites than from serum. The exposure of the inflammatory peritoneal fluid to the drug expressed by area under the concentration-time curve (AUC) was also subject to significant interindividual variation, ranging from 223 to 2332 μg/ml × min. However, the peritoneal AUC was correlated with serum AUC and with the systemic clearance of the drug. A significant relationship between gamma glutamyltranspeptidase and both systemic clearance and either the serum or the peritoneal AUC was found, suggesting that liver plays a role in drug disposition.

Evidence for qualitative abnormalities in high-density lipoproteins from myeloma patients: the presence of amyloid A protein could explain HDL modifications.

HDL apolipoproteins (apo) from normal subjects and patients with multiple myeloma were studied by isoelectric focusing (IEF) and by two-dimensional gel electrophoresis. Qualitative abnormalities were detected in myeloma HDL apolipoproteins. We observed two new bands not previously described in this disease. As determined by IEF and two-dimensional gel electrophoresis, the relative molecular weight of these two proteins was 12,600, with pI = 6.04 and 6.36, respectively. They correspond to two isoforms of serum amyloid A protein (SAA), as confirmed by western blot assay against specific antiserum to SAA. The high sensitivity of this assay revealed also other SAA isoforms. Our data are consistent with the hypothesis that major apolipoproteins of normal HDL, apo A-I and apo A-II, could be displaced by SAA isoproteins in myeloma HDL. This could lead structural changes in HDL.

Autoradiographic distribution of [14C]-labelled pimonidazole in rhabdomyosarcoma-bearing rats and pigmented mice

SummaryThe hypoxic cell radiosensitizer [2-14C] pimonidazole (2-nitro-α-(piperidinomethyl)-l-imidazole ethanol) was injected i.p. into pigmented mice and rats bearing transplanted rhabdomyosarcoma. The injected dose level was 200 mg/kg, and the delivered activity was 96 μCi/kg. Whole-body autoradiography was carried out on all animals. We noted an extensive whole-body distribution of radioactivity. At short intervals, the autoradiograms were characterized by an accumulation of radioactivity in the metabolic and exretory organs (liver, kidney, urinary tract, and intestinal content) as well as in lymphomyeloid tissues (thyroid gland, suprarenal gland, and hypophysis) and salivary glands. In pigmented mice, the uveal and biliary tracts were the highest labelled. The liver and particularly the renal medulla were identified as sites of retention of radioactivity. In the tumor the radioactivity was detected only in peripheral regions, with higher uptake in viable zones than in necrotic islets.

Pharmacokinetics and efficacy of i.v. and i.p. VM26 chemotherapy in mice bearing krebs II ascitic tumors

The pharmacokinetics and the efficacy of VM26 are studied following i.p. or i.v. administration in mice bearing Krebs II ascitic tumors. The i.p. inoculation of 30.10(6) Krebs II cells in Swiss mice leads to the formation of ascites. The effects of VM26 were dependent upon the route of administration. A 2 mg/kg i.p. single dose induces an equivalent per cent increase of median survival time than a 20 mg/kg i.v. single dose. The survival advantage of i.p. VM26 was found to be related to the pharmacologic benefit of i.p. administration. If local toxicity does not prove to be a major problem, i.p. VM26 may constitute a safe and practical mode of therapy in patients with intraabdominal tumors.