ABSTRACT
Cancer Procoagulant (CP), a cysteine proteinase which triggers blood coagulation by directly activating Factor X (FX) in the absence of Factor VII (F VII), has recently been isolated from rabbit V2 carcinoma and biochemically characterized. We have studied the procoagulant activity of tissue extracts from 4 murine experimental tumors in order to define whether or not a F VII-independent activity with cysteine proteinase characteristics was present. The tumors studied were: Lewis lung carcinoma (3LL), B16 melanoma (B16), JW sarcoma (JWS) and the M4 variant of the mFS6 fibrosarcoma (M4). Extracts from 3LL, B16 and JWS tumor initiated coagulation in both the presence and absence of F VII, their procoagulant activity was sensitive to iodoacetamide (1 mM) and mercury chloride (0.1 mM). The procoagulant of M4 extract was dependent on the presence of F VII and was not significantly affected by the cysteine proteinase inhibitors. An Ouchterlony double immunodiffusion study showed immunological cross-reactivity of all but M4 extracts to a polyclonal antibody to purified CP. The present study suggests that the procoagulant(s) present in the murine tumors 3LL, B16 and JWS are enzymatically and immunologically indistinguishable from cancer procoagulant of the rabbit V2 carcinoma.
Subject(s)
Blood Coagulation Factors/analysis , Endopeptidases/analysis , Neoplasm Proteins , Neoplasms, Experimental/enzymology , Animals , Cysteine Endopeptidases , Endopeptidases/immunology , Fibrosarcoma/enzymology , Lung Neoplasms/enzymology , Melanoma/enzymology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasm Metastasis , Neoplasms, Experimental/pathologyABSTRACT
Since the highly metastatic variant M4 of the mFS6 fibrosarcoma has the peculiar feature of generating larger amounts of immunoreactive thromboxane B2 (TxB2) than the non-metastatic variant (M9), we used the thromboxane synthase inhibitor dazmegrel (UK-38,485) in an effort to influence its metastatic potential. TxB2 formation by tumor cells freshly harvested from the primary tumor could be completely inhibited by drug addition in vitro. TxB2 generation was inhibited with a dose-response curve, 2 microM being the lowest dazmegrel concentration giving 100% inhibition. Chronic treatment of tumor-bearing mice with dazmegrel (150 mg/kg b.w. twice daily by gavage) from the day of tumor-cell implantation until killing of the animals caused a more than 10-fold reduction in serum TxB2 formation; TxB2 generation by tumor cells was also significantly depressed. This treatment, however, did not significantly modify either primary tumor weight or metastasis formation. Our data suggest that selective inhibition of thromboxane generation in either blood or tumor cells does not prevent spontaneous metastasis formation in the murine model studied.
