The human melanoma cell line A375M expresses the vitronectin receptor (aP3 integrin) on its cell surface. Treatment of A375M cells with either polyclonal or monoclonal anti-a,43 antibodies resulted in stimulation of invasion through basement membrane matrices in vitro. Similar treatment of these cells with a monoclonal anti-el antibody, which does not inhibit the adhesive function of the a,#3antigen, also stimulated invasion; however, anti-,83 antibody treatment had no effect. Furthermore, pretreatment of the cells with vitronectin or addition of vitronectin to the basement membrane matrix also resulted in stimulation of invasion. Similar treatments with fibronectin receptor antibody or fibronectin had no effect on invasion. Analysis of type IV collagenase expression in cells treated with anti-a4,33 antibody showed higher levels of both the secreted 72-kDa enzyme and its mRNA. Signal transduction through the a413 integrin could underlie the elevated expression of metalloproteinase and the enhanced invasion of A375M cells through basement membrane matrices.The three-step model for tumor cell invasion describes the initial process of the complex metastatic cascade in relatively simple terms: cell attachment to the extracellular matrix, proteolytic dissolution of the matrix, and movement of cells through the digested barrier (1). This process can occur repeatedly during the course of intra-and extravasation and can result in metastases at sites distant from the original tumor. The integrins, which are a family of cell-surface proteins that mediate cell-substratum and cell-cell adhesion, are important mediators of some of the interactions that constitute the metastatic process. The integrins are heterodimers of noncovalently linked a and ,8 subunits, each of which is a transmembrane protein (2-4). Eleven a and six 3 subunits have been identified; in various combinations they can produce at least 16 distinct integrins (5-7). Furthermore, a,B subunit can associate with multiple a subunits, and a single a subunit can become paired with more than one /3 subunit. In addition, more than one ligand can be bound by most integrins (5-8).While in vitro and in vivo comparisons between normal and malignant cells suggest that changes in integrin expression accompany malignant transformation (9), little correlation exists between the altered pattern of integrin expression and tumorigenesis (7). However, elevated expression of the a5/31 fibronectin receptor integrin is associated with lowered tumorigenicity (9,(10)(11)(12). Moreover, inhibition of integrin functions has suggested that integrins are important components of the metastatic process (7,(13)(14)(15)(16)(17)(18). Earlier, correlative observations suggest that the avI33 integrin (also known as the vitronectin receptor) is one of the integrins that plays a role in tumorigenicity and metastasis. Thus, elevated expression of this integrin is associated with invasive melanoma in vitro (7). We have explored the relationship between the function and expression of the av...

The primary objective of this phase 3 study was to determine whether postconsolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) improved the leukemia-free survival (LFS) of adult patients with acute myeloid leukemia (AML) in complete remission (CR). Three hundred twenty patients with AML (median age, 57 years; range, 18-84 years) were stratified by CR1 or subsequent CR (CR > 1) and randomly assigned to treatment with HDC/IL-2 or no treatment (control). Treatment comprised 10 21-day cycles with IL-2 (16 400 U/kg) plus HDC (0.5 mg); both compounds were administered by subcutaneous injection twice daily. Study arms were balanced for age, sex, previous treatment, leukemic karyotypes, time from CR to inclusion, and frequency of secondary leukemia. Three years after enrollment of the last patient, treatment with HDC/IL-2 was found to improve LFS over control in the study population (CR1 ؉ CR > 1, n ‫؍‬ 320; P < .01, log-rank test). For patients in CR1 (n ‫؍‬ 261), treatment significantly improved LFS (P ‫؍‬ .01) with 3-year LFS estimates of 40% (HDC/IL-2) compared with 26% (control

Transferrin receptor (TfR) has been shown to be significantly overexpressed in different types of cancers. We discovered TfR as a target for gambogic acid (GA), used in traditional Chinese medicine and a previously undiscovered link between TfR and the rapid activation of apoptosis. The binding site of GA on TfR is independent of the transferrin binding site, and it appears that GA potentially inhibits TfR internalization. Down-regulation of TfR by RNA interference decreases sensitivity to GA-induced apoptosis, further supporting TfR as the primary GA receptor. In summary, GA binding to TfR induces a unique signal leading to rapid apoptosis of tumor cells. These results suggest that GA may provide an additional approach for targeting the TfR and its use in cancer therapy.rapid apoptosis ͉ caspases ͉ target identification

Abstract. Human umbilical vein endothelial cells attach and spread on laminin-coated substrates. Affinity chromatography was used to identify the attachment receptor. Fractionation of extracts from surfaceiodinated endothelial cells on human lamininSepharose yielded a heterodimeric complex, the subunits of which migrated with molecular sizes corresponding to 160/120 kD and 160/140 kD under nonreducing and reducing conditions, respectively. The purified receptor bound to laminin and slightly less to fibronectin and type IV collagen in a radioreceptor assay. This endothelial cell laminin receptor was classified as an t~zB, integrin because monoclonal and polyclonal antibodies directed against the ct2 and/3, subunits immunoprecipitated the receptor. Cytofluorometric analysis arid immunoprecipitation showed that the ix2 subunit is an abundant integrin ~t subunit in the endothelial cells and that the ot subunits associated with laminin binding in other types of cells are expressed in these cells only at low levels. The ,v~, integrin appears to be a major receptor for laminin in the endothelial cells, because an anti-ix2 monoclonal antibody inhibited the attachment of the endothelial cells to human laminin. These results define a new role for the o~2 subunit in laminin binding and suggest that the ligand specificity of the tx2/3t integrin, which is known as a collagen receptor in other types of cells, can be modulated by cell type-specific factors to include laminin binding.