ABSTRACT
The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Doxorubicin/administration & dosage , Epirubicin/administration & dosage , Leukemia P388/drug therapy , Micelles , Poloxalene/analogs & derivatives , Animals , Chemical Phenomena , Chemistry, Pharmaceutical , Chemistry, Physical , Drug Carriers , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Drug Synergism , Female , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Multiple Myeloma/drug therapy , Neoplasm TransplantationABSTRACT
In 70 patients with stage III multiple myeloma (MM) the authors studied spontaneous and lipopolysaccharide-induced production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by blood and bone marrow mononuclear cells, concentration of parathyroid hormone and vitamin D3 in the serum. Bone marrow density was measured at photon absorption (Gambro), in patients treated with osteoprotectors bonefos and oxidevit before and after therapy (3.5-6 month course). It is shown that in MM there is a pathogenetic association between production of osteotropic IL-1, IL-6 and bone demineralization. The cases with reduced concentration of Ca and P ions in the serum (4 and 5.7% of patients, respectively) and increased PTH concentration (7%) suggest the existence of new, extratumor mechanisms of osteolysis. It is found that biphosphonates are optimal osteoprotectors. Bonefos (chlodronat, Lieras, Finland) arrests osteolysis proved by a significant increase of bone marrow density and clinical effect.
Subject(s)
Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Osteolysis/drug therapy , Osteolysis/etiology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Density/drug effects , Bone Marrow/chemistry , Cholecalciferol/blood , Female , Humans , Hydroxyproline/urine , Interleukin-1/analysis , Interleukin-6/analysis , Male , Middle Aged , Multiple Myeloma/metabolism , Osteolysis/metabolism , Parathyroid Hormone/bloodABSTRACT
Constitutive and lipopolysaccharide (LPS)--induced production of interleukin (IL)-1 and IL-6 have been investigated in peripheral blood (PB) and bone marrow (BM) of patients with multiple myeloma (MM) and PB of health donors. The level of these cytokines has been higher in MM in comparison with norm. Monocytes of PB of patients with MM have been more stimulated by LPS than those of health people. When adherent and nonadherent cells have been cultured apart, there not have not been any differences in constitutive IL-6 production between compared groups. The important role of cell-cell interactions in regulation of IL-6 production is proposed. High level of IL-6 in BM of patients with MM is conditioned by mutual stimulation of adherent and nonadherent cells.
Subject(s)
Bone Marrow/metabolism , Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Leukocytes, Mononuclear/metabolism , Multiple Myeloma/metabolism , Aged , Bone Marrow/drug effects , Bone Marrow Cells , Cell Communication/physiology , Cells, Cultured , Female , Humans , Kinetics , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/pharmacology , Male , Middle Aged , Multiple Myeloma/blood , Multiple Myeloma/pathology , Reference ValuesABSTRACT
The interleukin-6-(IL-6)-alpha dependent B-cell heterohybridomas were obtained by the fusion of X65.Ag8.653 cells with spleen cells from August rats immunized with lipopolysaccharide E. coli. One of these hybridomas (D6C8) was found to be most dependent on IL-6 for its surviving and growth. Human recombinant IL-1 beta and tumor necrosis factor-alpha could not induce the in vitro growth of this cell line. Presence of elevated level of IL-6 was demonstrated in the sera of patients with rheumatoid arthritis. A specific and sensitive detection of the IL-6 activity in test samples makes it possible to study the presence and role of IL-6 in various immunological disorders.
