Improved therapeutic responses for liposomal doxorubicin targeted via thrombospondin peptidomimetics versus untargeted doxorubicin.

New therapies in cancer treatment are focusing on multifaceted approaches to starve and kill tumors utilizing both antiangiogenic and chemotherapeutic compounds. In this work, we searched for a peptide vector that would home liposomes both to endothelial and tumor cells. [Abu6]TSPB and [Abu6]TSPA, aspartimide analogs of natural sequences of TSP-1 and TSP-2, respectively, were tested for adhesion of tumor and endothelial cells, in vivo and in vitro antiangiogenic effects, and in vivo antitumor action.

In vitro effects of SIKVAV retro and retro-enantio analogues on tumor metastatic events.

The SIKVAV peptide, located on the long arm of the laminin alpha1 chain, promotes cell adhesion, invasion and migration of tumor and endothelial cells, resulting in tumor growth, angiogenesis and metastasis. In this paper, we report the synthesis of the SIKVAV peptide and its retro (reverse l-amino acid order) and retro-enantio (reverse d-amino acid order) analogues and their effect on three critical steps in the metastatic process: cell-extracellular matrix protein (ECM) adhesion, cell migration and homotypic cell adhesion, using B16F10 melanoma cells. Results show that all peptides compete with laminin-1 cell attachment, but only SIKVAV induces peptide-cell adhesion.

Synthesis of a series of 3-cyanopropionamides and 4-imino-gamma-butyrolactams and evaluation of their function as modulators of multidrug resistance.

The synthesis of the 3-cyanopropionamides 3a and 3b, of the 2,2-dimethyl-3-cyanopropionamides 4a-4c and of the 4-imino-gamma-butyrolactams 5a and 5b (cyclic functional isomers of 3-cyanopropionamides) is described. The amides 3a and 3b were obtained by aminolysis of the corresponding acid chlorides, which are accessible via hydrolysis of the ethyl esters to the acids. This methodology was not used for the synthesis of the amides 4a-4c owing to steric hindrance to hydrolysis in the corresponding ethyl esters.

Sensitizing properties of new N-(2-arylalkyl) propionamides in drug-sensitive and multidrug-resistant tumor cells.

The propionamides 5 and 6 have been synthesized and tested for stimulation of antitumor drug activity. 5 and 6b increase vincristine cytotoxicity in drug-sensitive murine tumor cells; 5 also increases the toxicity in multidrug resistant cells. Dissimilar trends in sensitive and resistant cells have been observed for the stimulating activity of several propionamides of this family and structurally related verapamil with their molar refractivity, suggesting different size requirements for the sensitizers in sensitive and resistant cells.

Role of cell cholesterol in modulating vincristine uptake and resistance.

The relationship between cell-membrane permeability to vincristine and cholesterol/phospholipid levels was studied in L5178Y murine leukemic lymphoblasts and in 2 multidrug-resistant cell sublines, VCR/P60 and VCR/P200, which expressed increasing levels of vincristine resistance. The uptake of 3H-vincristine was measured in all cell lines and in cholesterol-depleted and -reloaded L5178Y and VCR/P200 cells. The initial rate of drug entry in resistant cells was lower than that measured in the parental cell line and it decreased as the relative resistance increased.

Vincristine cellular pharmacokinetic changes associated with multidrug resistance.

The correlation between vincristine cellular pharmacokinetics and its biological action was analyzed in L5178Y cells and in a multidrug resistant subline (VCR/G40) at the nM drug concentration range attained in serum during the clinical use of the drug. The reduced rate of drug influx and the higher drug efflux measured in VCR/G40 cells justify the lower drug accumulation characterized in these cells compared to the parental cells. Nevertheless this does not seem to be the sole reason accounting for the resistance expression since similar cytotoxic effects of vincristine on both cell lines were only attained when the intracellular drug concentration was ten times higher in resistant than in parental cells.

Simultaneous changes in various mechanisms that mediate the cell incorporation of folate compounds account for low levels of resistance to methotrexate.

Changes in the mechanisms of folate incorporation were studied in cells treated with low concentrations of methotrexate in order to evaluate their contribution to the development of resistance to antifolate drugs. The uptake of methotrexate via reduced-folate system, the membrane-associated high-affinity folate binding capacity and the activity, levels and affinity for methotrexate of dihydrofolate reductase were measured in L5178 murine leukemic lymphoblasts and in a subline, MTX/R16, 16 times more resistant to methotrexate which was isolated after a short exposure to the antifolate. Various simultaneous changes were characterized in MTX/R16 cells which co-participated in the development of resistance: a decreased affinity of the carrier for methotrexate uptake via the reduced-folate system of entry, the increase of dihydrofolate reductase activity and levels and a two-fold increased expression of a membrane-associated high-affinity folate-binding protein (mFBP).

Comparative uptake, retention and action of vincristine, vinblastine and vindesine on murine leukaemic lymphoblasts sensitive and resistant to vincristine.

1. The uptake and retention of vincristine (VCR), vinblastine (VBL) and vindesine (VDS) were evaluated comparatively with respect to their cytotoxic action on a murine lymphoblastic leukaemia (L5178Y). 2.

Evolution of acute lymphoblastic leukemia in mice treated with carrier-bound methotrexate and levamisole.

The cytotoxic and antitumoral activities of free or bound to bovine serum albumin (BSA) methotrexate (MTX) and the influence of levamisole (LMS) on these were assayed on murine leukemia. Whereas the in vitro cytotoxic action of MTX was reduced by its conjugation to BSA, in vivo a single dose of 15 mg/kg MTX, which lacked therapeutic effect on tumor-bearing mice, increased the mean survival time (MST) of the animals when given as MTX-BSA. Levamisole slightly increased the MST of the tumor-bearing animals when administered as a 10 mg/kg single dose 7 days after the tumor inoculation.

[Method for selecting cells during various phases of the mitotic cycle].

Exponentially growing L5178Y cells in suspension culture were separated according to their position in the cell cycle on the basis of their volume with a velocity sedimentation method in which a linear and continuous ficoll gradient was used. Highly purified populations of G1 and S cells were obtained, containing about 90% G1 phase cells and 80% S phase cells. The method is rapid and a larger number of cells can be easily processed with no loss of viability.