Integrins of the ␣v family, such as ␣v3 and ␣v5, are implicated in tumor-induced angiogenesis; but their role in tumor growth has not been fully explored. CNTO 95 is a fully human antibody that recognizes the ␣v family of integrins and is likely to be less immunogenic in humans compared to chimeric or humanized antibodies. CNTO 95 bound to purified ␣v3 and ␣v5 with a
Integrins are heterodimeric cell adhesion receptors that mediate intercellular communication through cell-extracellular matrix interactions and cell-cell interactions. Integrins have been demonstrated to play a direct role in cancer progression, specifically in tumor cell survival, tumor angiogenesis, and metastasis. Therefore, agents targeted against integrin function have potential as effective anticancer therapies. Numerous anti-integrin agents, including monoclonal antibodies and small-molecule inhibitors, are in clinical development for the treatment of solid and hematologic tumors. This review focuses on the role of alpha(v) integrins in cancer progression, the current status of integrin-targeted agents in development, and strategies for the clinical development of anti-integrin therapies.
Initially, prostate cancer is androgen dependent. However, most cases progress to an androgen-independent state through unknown mechanisms. Interleukin-6 (IL-6) has been associated with prostate cancer progression including activation of the androgen receptor (AR). To determine if IL-6 plays a role in the conversion of prostate cancer from androgen dependent to androgen independent, we established androgen-dependent LuCaP 35 human prostate cancer xenografts in nude mice, castrated the mice, and blocked IL-6 activity using a neutralizing antibody (CNT0328) for a period of 18 weeks. IL-6 inhibition increased survival of mice and inhibited tumor growth, as reflected by decreased tumor volume and prostatespecific antigen levels, compared with that in mice receiving isotype control antibody. To test the effect of IL-6 inhibition on the conversion from androgen dependent to androgen independent, tumor cells from the treated mice were assessed for their androgen dependence both in vitro and by implanting them into sham-operated or orchiectomized mice. Tumor cells derived from the isotype-treated animals converted to androgen-independent state, whereas tumor cells from the anti-IL-6 antibody-treated mice were still androgen dependent in vitro and in vivo. Although there was no difference in AR levels between the androgen-independent and androgen-dependent tumors, IL-6 inhibition promoted both apoptosis and inhibited cell proliferation in tumors and blocked the orchiectomyinduced expression of histone acetylases, p300 and CBP, which are AR cofactors. These data show that IL-6 contributes to the development of androgen independence in prostate cancer and suggest that it mediates this effect, in part, through modulation of p300 and CBP. (Cancer Res 2006; 66(6): 3087-95)
These preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.
IL-6 is a multifunctional cytokine implicated in several cancers. IL-6 is a growth factor for certain tumors and contributes to drug resistance, cachexia and bone resorption. Cachexia is characterized by progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. We have developed CNTO 328 (cCLB8), a humanmouse chimeric MAb to IL-6 (K d approx. 10 ؊12 M) that inhibits IL-6 function. A phase I study with CNTO 328 in multiple myeloma patients demonstrated that the antibody was safe and had a circulating half-life of approximately 17 days. Since IL-6 is implicated in cachexia, we hypothesized that CNTO 328 could inhibit tumor-induced cachexia. We used 2 human tumor-induced cachexia models in nude mice. In the first model, human melanoma cells were inoculated in female nude mice. Control treated animals lost 19% (؎7.7%) body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)-treated animals lost only 1.5% (؎1.3%) body weight from day 0 to day 31 (p ؍ 0.023). Cachexia (wasting syndrome) is a debilitating state of involuntary weight loss that is characterized by hypercatabolism of the body's carbon sources, proteins and lipids, for conversion into energy. 1 Cachexia is induced by a variety of pathologic conditions, including cancer, where an estimated 30% of cancer deaths are attributed to cachexia. Tumor necrosis factor (TNF)-␣, IL-1, IFN-␥ and IL-6 contribute to many of the host changes seen in cancer cachexia, including loss of appetite, loss of body weight and induction of acute-phase proteins. 2 These cytokines induce cachexia by altering the metabolism of lipids and proteins. IL-6 is a 26 kDa protein with a broad range of activities, involving not only immunomodulation but also hemostatic, neuroendocrine and cancer-associated disorders. 3 IL-6 is an acute phase-inducing cytokine that is secreted to a large extent by human adipose tissue under noninflammatory conditions. 4 It also influences atrophy and increases catabolism of muscle protein. IL-6 is expressed together with its receptor in neurons of hypothalamic nuclei that regulate body composition. IL-6 levels in serum correlate with body mass index (BMI), and IL-6-deficient mice developed mature-onset obesity. 4 Although several studies have suggested that host-derived IL-6 contributes to cachexia, the role for tumor cell-secreted IL-6 in cachexia is less clear.IL-6 is also implicated in regulating the growth and differentiation of several malignant diseases. The ability of IL-6 to mediate tumor cell survival and disease progression has been demonstrated by the inhibitory effects of an anti-IL-6 MAb on tumor growth both in vitro and in vivo. Blockade of IL-6 can inhibit growth of human glioblastoma cells in vitro. 5 Using the same approach, it was shown that injection of an antihuman IL-6 MAb prolonged the survival of human lymphoma-bearing mice. 6 Several clinical trials using monoclonal antibodies (MAbs) against IL-6 have been conducted on various diseases, including plasma cell leukemia, multiple myeloma, B-lymphop...
The extracellular matrix of the normal adult brain lacks expression of most of the adhesive glycoproteins that are known to promote cell attachment, and it has been thought that the malignant invasion of astrocytoma tumor is mediated primarily by remodeling of the matrix by the tumor cells. It has been reported, however, that normal brain neuropil does contain a protein(s) that promotes cell attachment. Therefore, we explored the possibility that the cell attachment protein, osteopontin, is expressed in the normal human brain. Here, we report that osteopontin is expressed in the cortical gray and white matter of normal adult brain, with the levels of osteopontin expression being equivalent to those in malignant astrocytic tumor biopsies as assessed by Western blot analysis. Immunoblotting identified osteopontin polypeptides with relative molecular weights of 60-and 65-kDa in normal brain white matter and in astrocytic tumors, with an additional 70-kDa polypeptide being identified in normal cortical gray matter and in some astrocytic tumors. Recombinant osteopontin was found to promote attachment of U-251MG human malignant astrocytoma cells in a process that was inhibited by anti-integrin monoclonal antibodies anti-␣v3 (75%), anti-␣v5 (80%), and anti-␣5 (40%). On attachment, integrins ␣v5 and ␣v3 localized to focal adhesions, and there was an alteration in cell morphology with the formation of lamellae-like processes. The attachment was associated with activation of Rac in a slow and prolonged fashion and rapid activation of Rho. Similarly, integrins ␣v5 and ␣v3 localized to focal adhesions on attachment of the U-251MG cells to vitronectin, but on this substrate, the cells assumed a spread and flat morphology, and there was rapid activation of both Rac and Rho. Extracts of normal brain white matter were capable of promoting haptotactic migration, and this response was inhibitable by monoclonal antibodies anti-␣v3 and anti-␣5. Depletion of the osteopontin in these extracts abrogated the haptotactic response significantly (50%). These data indicate that the cell attachment protein, osteopontin, is expressed in the normal adult brain and that it has the potential to promote malignant astrocytoma cell invasion.
Proteins that inhibit glycoprotein (GP) IIb/IIIa mediated platelet aggregation have been purified from the venom of two snake species. A small platelet aggregation inhibitor (p1.AI), multisquamatin (Mr = 5,700), was purified from Echis multisquamatus venom by hydrophobic interaction HPLC and two steps on C18 reverse phase HPLC. A larger p1.AI, contortrostatin (Mr = 15,000), was purified by a similar HPLC procedure from the venom of Agkistrodon contortrix contortrix. Both p1.AIs inhibit ADP-induced human, canine and rabbit platelet aggregation using platelet rich plasma (PRP). Multisquamatin has an IC50 of 97 nM, 281 nM and 333 nM for human, canine and rabbit PRP, respectively. Contortrostatin has an IC50 of 49 nM, 120 nM and 1,150 nM for human, canine and rabbit PRP, respectively. In a competitive binding assay using 125I-7E3 (a monoclonal antibody to GPIIb/IIIa that inhibits platelet aggregation) both contortrostatin and multisquamatin demonstrated GPIIb/IIIa specific binding to human and canine platelets. The IC50 for contortrostatin displacement of 7E3 binding to human and canine GPIIb-/IIIa is 27 nM and 16 nM, respectively and for multisquamatin it is 3 nM and 63 nM, respectively. Our results indicate that both p1.AIs inhibit platelet aggregation by binding with high affinity to GPIIb/IIIa.
Thromboembolism is one of the most common causes of death in cancer patients. Among the most frequent thrombotic complications in patients with cancer are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and thrombocytosis. Clearly, these complications arise as tumor cells interact with almost all components of the hemostatic system including platelets. Platelets participate in tumor progression by contributing to the metastatic cascade, protecting tumor cells from immune surveillance, regulating tumor cell invasion, and angiogenesis. Platelets contain one of the largest stores of angiogenic and mitogenic factors and the tumor vasculature is leaky, which allows platelets to come in contact with the tumor and deposit multiple angiogenic factors including vascular endothelial growth factor (VEGF) and thrombin to tumor cells, which in turn contributes to tumor progression. This article reviews the recent literature on how platelets contribute to tumor growth, angiogenesis, and metastasis.
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