Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains the major obstacle for successful treatment of cancer. Inhibition of Pgp transport is important for higher efficacy of anticancer drugs. Lipophilic cationogenic amines with at least one tertiary N atom, such as verapamil, are classical PgP-blocking agents. In a search for novel accessible compounds potent against MDR tumor cells, we synthesized a series of arylalkylamines that contain isoprenoid side chains of different length. Two out of seven new analogues of the known N,N'-bis(3,4-dimethoxybenzyl)-N-solanesylethylenediamine (SDB-ethylenediamine), namely, compounds with C10 and C15 side chains, at low micromolar concentrations were preferentially toxic for several mammalian tumor cell lines that acquired MDR during prolonged drug selection. Moreover, at noncytotoxic concentrations, these compounds potently sensitized MDR cells to Pgp substrates vinblastine and adriamycin. We conclude that these analogues of SDB-ethylenediamine may have dual therapeutic advantage because (i) they are preferentially toxic for MDR cells when administered alone and (ii) they potentiate the cytotoxicity of Pgp-transported anticancer drugs.

We studied the expression of genes encoding vascular endothelial growth factors VEGF-A, VEGF-C, VEGF-D and their receptors in cell cultures of human multiple myeloma IM9, RPMI 1640, RPMI 8226. The studied cells did not differ by the expression of growth factors. Expression of VEGFR1 receptor was detected only in IM9 cells and VEGFR2 and VEGFR3 receptors were not expressed in multiple myeloma cells. A dependence between the aberrant CD45/CD56 phenotype of human multiple myeloma cells and VEGFR1 expression in them was revealed. The only VEGFR1-positive IM9 cell culture was most resistant to Velcade (bortezomib).

The role of cellular interactions in the resistance of Djungurian hamster cells to colchicine (CH) and in the efficiency of P-glycoprotein function was studied. Mixtures of CH-resistant and CH-sensitive cells as well as control unmixed cells were propagated for 3 days and the sensitivity of the cells to CH was measured by colony forming assay. Identification of individual subpopulations was possible due to genetic marker (6TG-resistance). The data show that the survival of CH-sensitive cells in CH-supplemented medium increased after co-cultivation with CH-resistant counterparts. To measure Pgp activity the fluorescent dye RH123 and FACScan analysis were used. Pgp-mediated RH123 efflux increased after co-cultivation of CH-sensitive and CH-resistant cells.

To study the acquired radioresistance of tumor cells, a model system of two cell lines, Djungarian hamster fibroblasts (DH-TK-) and their radioresistant progeny, was established. The progeny of irradiated cells were isolated by treating the parental cell monolayer with a single dose of 20 Gy (PIC-20). The genetic and morphological features, clonogenic ability, radiosensitivity, cell growth kinetics, ability to grow in methylcellulose, and tumorigenicity of these cell lines were compared. The plating efficiency of PIC-20 cells exceeded that of DH-TK- cells. The progeny of irradiated cells were more radioresistant than parental cells. The average D0 for PIC-20 cells was 7.4 +/- 0.2 Gy, which is three times higher than that for parental cells (2.5 +/- 0.1 Gy). Progeny cell survival in methylcellulose after irradiation with a dose of 10 Gy was 15 times higher than that of DH-TK- cells. In contrast to parental cells, the progeny of irradiated cells showed fast and effective repopulation after irradiation with doses of 12.5 and 15 Gy. The tumor formation ability of irradiated progeny cells was higher than that of parental cells; after 15 Gy irradiation, PIC-20 cells produced tumors as large as unirradiated progeny of irradiated cells, whereas the tumor development of DH-TK- cells diminished by 70%. High radioresistance of progeny of irradiated cells was reproduced during the long period of cultivation (more than 80 passages). The stability of the radioresistant phenotype of PIC-20 cells allows us to investigate the possible mechanisms of acquired tumor radioresistance.

Coexpression of two mRNA isoforms for insulin-like growth factor-1 (IGF-1A and IGF-1B) and expression of YB-1 mRNA were analyzed in the bone marrow aspirates from 19 patients with multiple myeloma. It was shown that mRNA isoforms for IGF-1A and IGF-1B were mainly expressed in samples with hyperexpression of YB-1 mRNA, and, on the contrary, practically were not expressed (except sporadic cases) in samples with low level of YB-1 mRNA expression. Coexpression of mRNA isoforms for IGF-1A and IGF-1B were observed in 80% patients with multiple myeloma.