Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.
SummaryA splice variant of CD44 (CD44v) originally discovered on metastases of a rat pancreatic adenocarcinoma (BSp73ASML) has been shown by transfection to confer metastatic behavior to nonmetastatic tumor cells (Gfinthert U., M. Hofmann, W. Rudy, S. Reber, M. Z611er, I. Haussmann, S. Matzku, A. Wenzel, H. Ponta, and P. Herrlich. 1991. Cell. 65:13). A monoclonal antibody (mAb), 1.1ASML, to the metastasis-specific domain of the CD44v molecule retards growth of lymph node and lung metastases of the metastatic tumor line BSp73ASML, and can efficiently prevent formation of metastases by the transfected line. The antibody is only effective when given before lymph node colonization. Anti-CD44v does not downregulate the expression of CD44v, and prevention of metastatic growth by antioCD44v is not due to activation of any kind of immune defense. We suggest that the mAb interferes with proliferation of metastasizing tumor cells in the draining lymph node, most probably by blocking a ligand interaction. The interference with metastatic spread will greatly facilitate the exploration of the function of CD44v and, in particular, may also open new strategies for the therapy of human metastases.C D44 is an integral membrane glycoprotein (1-7), originally described as a homing receptor of lymphocytes (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Beside the involvement of CD44 in adhesion of lymphocytes to specialized endothelial cells, CD44 is known to bind to hyaluronate and probably also to collagen (7,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), suggesting roles in the interaction between cells and extracellular matrix. Moreover, several variants of CD44 with additional extracellular domains have been detected in a variety of tissues and frequently on tumor cells (1,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40).The fact that metastatic spread involves interaction between tumor cells and extracellular matrix as well as between tumor cells and endothelial cells has led to the hypothesis that especially the variant forms of CD44 may be involved in the process of metastatic spread (32, 35). Starting from a metastasisspecific mAb (1.1ASML) (41) that has been raised against the highly metastatic pancreatic adenomcarcinoma line BSp-73ASML (42), we have cloned a splice variant of CD44 (CD44v) 1 (35). The splice variant carries an expanded extracellular domain. Overexpression of this variant in any one of several nonmetastatizing tumor cell lines confers full metastatic behavior to these cells (35, 42a).l Abbreviations used in this paper: CD44s, standard CD44; CD44v, splice variant of CD44.We now report on the specific interference of mAb 1.1ASML with metastasis formation. Intravenous injections of 1.LASML inhibited or prevented the colonization of lymph nodes and lung. No evidence for an antibody-mediated immune attack could be detected. Furthermore, 1.1ASML did not interfere with surface expression of CD44v. The data support the view that CD44v catalyzes embedding/outgrowth of tumor cells in the draining lymph nodes. Materials and M...
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