oxazolone and Lung-Neoplasms

Phorbol esters which activate protein kinase C (PKC) have been shown to enhance experimental lung metastasis. Therefore, it was reasoned that inhibitors of PKC might also modulate metastasis. We have investigated this possibility using a PKC inhibitor, MDL 27,032 [4-propyl-5(4-pyridinyl)-2(3H)-oxazolone], as well as staurosporine and H-7. Treatment of B16F1 murine melanoma cells with MDL 27,032 for 24 h in culture and subsequent i.v. injection of the cells into mice resulted in greater than 90% inhibition of lung metastasis. Inhibition of metastasis was time dependent, with 90% of maximum inhibition occurring by 8 h of incubation. The 50% inhibitory concentration (IC50) for inhibition of metastasis with MDL 27,032 was 7 microM, a value similar to that for the inhibition of B16F1 membrane-associated PKC (IC50 = 13 microM) but not cytosolic PKC (IC50 = 54 microM). B16F1 cells treated with MDL 27,032 for 24 h were less adherent than untreated cells to extracellular matrix/basement membrane proteins. Adhesion to fibrinogen and collagen IV was inhibited (IC50 = 6 microM and 48 microM, respectively) by MDL 27,032, whereas adherence to laminin and fibronectin was not affected, indicating that the drug affects specific adhesion molecules. MDL 27,032-treated cells were also found to be less adherent than untreated cells to human umbilical vein endothelial cells. The phosphorylation of an 80-kDa B16F1 cell plasma membrane protein was stimulated under conditions known to stimulate PKC activity, and MDL 27,032 inhibited this phosphorylation in a dose-dependent manner. MDL 27,032 was more potent than H-7 for the inhibition of metastasis but was significantly less potent than staurosporine. These results support the hypothesis that there is a critical role for PKC-mediated phosphorylation of cell surface adhesion receptors in metastasis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Alkaloids; Animals; Cell Adhesion; Isoquinolines; Lung Neoplasms; Melanoma, Experimental; Membrane Proteins; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Oxazoles; Oxazolone; Phosphorylation; Piperazines; Protein Kinase C; Pyridines; Staurosporine; Time Factors

The effect of microwave whole-body hyperthermia was examined on the takes of tumor after i.v. administration of the tumor single cell suspension. It was shown that the longer the exposure to hyperthermia treatment the higher the number of lung nodules obtained by injection of the same dose of tumor cells. Also, the expression of contact hypersenstivity to oxazolone was strongly inhibited after hyperthermia treatment. It was documented that it is possible to transfer the diminished resistance to tumor with bone marrow, whereas impaired responsiveness to oxazolone was transferred with spleen cells or thymocytes.

Topics: Animals; Bone Marrow; Hot Temperature; Immunization; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Microwaves; Neoplasm Transplantation; Oxazolone; Sarcoma, Experimental; Skin Tests; Spleen; Thymus Gland; Transplantation, Homologous