Recent Patents on Anti-Cancer Drug Discovery, 2007, 2, 73-78

73

New Perspectives in the Treatment of Melanoma: Anti-Angiogenic and Anti-Lymphangiogenic Strategies Floriana Facchetti, Elena Monzani and Caterina A.M. La Porta1,* Department of Biomolecular Science and Biotechnology, University of Milan, Milan 20133, Italy Received: December 27, 2005; Accepted: September 22, 2006; Revised: October 31, 2006

Abstract: Melanoma is a significant, worldwide growing public health burden. Single-agent chemotherapy or immunotherapy remains the treatment of election for this disease when systemic therapy is offered. Malignant melanoma of the skin is distinguished by its capability to early metastatic spread by means of lymphatic vessels to regional lymph nodes. Herein new accomplishments on the role of lymphangiogenesis and of angiogenesis in cutaneous melanoma will be discussed, together with the possible application of these discoveries in developing prognostic and therapeutic tools in melanoma metastasis. Furthermore, the present review will summarize the main angiogenic inhibitors reported in the recent patents (2003-2005), with special emphasis on the aspects which have important implications for the prognosis and the treatment of human melanomas.

n tio

Keywords: Melanoma, angiogenesis, lymphangiogenesis. INTRODUCTION Malignant melanoma incidence is increasing in the US, Europe and Australia [1-4]. Surgery remains the cornerstone of treatment for patients with loco-regional disease. However, only a few patients with advanced disease may be cured by surgery, and the majority of patients die [5, 6].

oxygen and nutrients for malignant tumor growth, invasion, and metastasis [12]. Whereas blood vessel growth is tightly controlled under physiological conditions, tumor progression is frequently associated with the acquisition of an angiogenic phenotype, which in turn is associated with a switch in the balance of pro- and antiangiogenic factors. These factors may be specific for distinct tumor types and tumor localizations, and may be altered during tumor progression [13].

u rib

t s i D r

TRADITIONAL CHEMOTHERAPIC AGENTS

Bayer describes dacarbazine, which belongs to the group of drugs called alkylating agents, used as standard of melanoma care for many years. Response rates of 7-13% have been reported in recent large phase III trials, with a further 15-28% of patients having stable disease [7,8]. However, few responses are longstanding.

o F t o N

A number of randomised trials failed to show a survival advantage for combination therapy over single-agent treatment [9-11]. Combination therapy is associated with an increased response rate, but also significantly increased toxicity resulting in increased numbers of hospital admissions. Immunotherapy continues to be evaluated in metastatic disease such as interferon (IFN)-alpha 2b and IL-2.

In conclusion, the majority of patients with advanced malignant melanoma requiring systemic therapy, singleagent treatment remains the treatment of choice. However, combination therapy may be warranted in certain circumstances such as when significant tumor shrinkage is a primary aim. ANTI-ANGIOGENIC AGENTS The induction of angiogenesis- the generation of new capillary blood vessels from pre-existing vessels- is generally considered as essential to ensure the supply of

*Address correspondence to this author at the Department of Biomolecular Science and Biotechnology, Celoria 26, 20133, Milan, Italy; E-mail: [email protected]

1574-8928/07 $100.00+.00

New blood vessel formation is a prominent feature of human cutaneous melanomas, indicating that these tumors have angiogenic activity [14]. The observation that cutaneous melanoma cells acquire the capacity to actively induce the growth of new blood vessels dates back to the earliest days of tumor angiogenesis research [15-17]. The clinical and prognostic significance of tumor angiogenesis for melanoma progression and metastasis, however, has remained controversial [18]. Contradictory results might be explained by the non-standardized assessments of tumor vascularity and by the variety of detection methods used to visualize tumor-associated blood vessels. Moreover, recent evidence has shown that the extent of vascularization does not discriminate between benign premalignant and malignant epithelial experimental and human skin tumors [19-21]. Importantly, none of the studies published on melanoma blood vessel quantification have included the - recently discovered - molecular markers that can be used to specifically detect blood vessels and lymphatic vessels in tissue sections [22, 23]. Many angiogenic factors were demonstrated to be synthesized by melanoma cells, including VEGF, bFGF, IL8, PDGF. The specific biological function of several of these factors has been evaluated in both in vitro angiogenic models and in xenograft models. For instance knockdown of VEGFR-2 and Tie-2 with an intrabody was demonstrated to reduce tumor growth and angiogenesis in a human melanoma xenograft model [24] and a different modulation © 2007 Bentham Science Publishers Ltd.

74

Recent Patents on Anti-Cancer Drug Discovery, 2007, Vol. 2, No. 1

of cytokines such as TGFbeta 1 or matrix-metalloproteinase such as gelatinase A has been shown to occur in a different manner between black and white metastasis [25]. Recently, a highly patterned system of vascular channels, lined externally by tumor cells, was observed in some aggressive human uveal and cutaneous melanomas [26]. This feature, termed “vasculogenic mimicry” was also observed after injection of melanoma cells into an ischemic micro environment that was surgically induced in the hind limbs of nude mice [27]. Formation of tubular networks were created in vitro by growing melanoma cells in three-dimensional cultures [28]. Multiple proangiogenic factors are produced by primary cutaneous melanoma cells such as VEGF whose expression appears to be increase during the transition from horizontal to vertical growth phase or metastasis [29-32], bFGF detected in metastatic and primary invasive melanomas [33], IL-8 that was found to be absent in normal epidermis and in benign melanocytic lesions, but was expressed in high levels of the majority of cutaneous melanoma [34]. Furthermore, down-regulation of endogenous angiogenesis inhibitors has been observed in several epithelial cancers, and it has been proposed that it might enhance tumor progression [34]. Thalidomide has anti-angiogenic and immunomodulatory proprieties and has been used successfully in the treatment of Kaposi’s sarcoma, myeloma and renal cancer [35,36]. Recent trials in melanoma, in which thalidomide was added to temozolomide (describes by Schering Corporation) reported a trend toward superior response rates and survival when the combination is compared with temozolomide monotherapy [37,38]. Temozolomide exerts its anticancer activity through the methylation of DNA at the O6 position of guanine residues. Considering the increase in efficacy with no increase in toxicity, temozolomide-thalidomide was recommended for further study.

Facchetti et al.

lymphatic vessels and the discovery of molecules that can drive lymphatic vessel growth [46-52]. Vascular remodelling associated with lymphangiogenesis and angiogenesis seems to involve a similar process. In response to molecular mediators, both lymphatic and vascular endothelial cells proliferate and migrate toward a stimulus as the extracellular matrix is degraded, followed by association of the endothelial cells into tube-like structures [53]. New production and realignment of the extracellular matrix and controlled apoptosis at appropriate sites are required for blood vascular and lymphatic system formation. Besides using similar processes of remodelling, blood and lymphatic vessels are closely associated in vivo. Process in understanding lymphangiogenesis has been hampered by the very similar characteristics of blood and lymphatic vessels in tissue section and it is made difficult by the lack of lymphatic-specific markers [54]. Furthermore, more accurate and simplified lymphatic vessel identification has recently been made possible by the discovery of molecules that are specifically expressed by lymphatic endothelium. Vascular endothelial growth factor receptor-3 (VEGFR-3) is predominantly expressed on lymphatic endothelium in normal adult tissue [55, 56] (Fig. 1). In particular, VEGF-C and VEGF-D members of VEGF family of secreted glycoproteins have been identified as regulators of lymphangiogenesis in mammals [56] (Fig. 1). The receptor for VEGF-C and -D is VEGFR-3 [57] (Fig. 1). The lymphatic receptor for hyaluronan, LYVE-1, has been reported to be a specific marker of lymphatic vessels and is thought to function in transporting-hyaluronan from the tissue to the lymph [58, 59, 60]. The transcription factor Prox 1 although required for lymphatic vessel development and expressed on lymphatic endothelium [61], is also expressed in other cell types and tissues, including hepatocytes and liver [62] and lens tissue [63], and is therefore of limited use immunohistochemically to identify lymphatic vessels. Podoplanin and desmoplakin have been reported as markers for lymphatic endothelium, but they also react with other cell types [6469]. In summary, a more extensive range of markers for lymphatic endothelium is now available: it should be of aid in defining the role of lymphatic vessels in tumor biology.

u rib

t s i D r

o F t o N

Lenalidomide (CC-5013) or Revlimid described by Calgene Corporation is a potent analogue of thalidomide that produces T-cell stimulation and has shown single-agent activity in melanoma [39,40].

MEDI-522 is a humanised monoclonal antibody to alphaVbeta3 integrin [41,42], and a randomised phase II trial of dacarbazine and MEDI-522 has completed accrual and the results are awaited. Semaxanib (SU5416) is a selective inhibitor of VEGF receptor 2 (VEGFR-2) and kit receptor tyrosine kinase. A recent phase II study of 31 patients with melanoma showed that it is well tolerate [43]. Bevacizumab or Avastin described by Genentech is a monoclonal antibody against VEGF that has shown a significant survival advantage when combined with chemotherapy in advanced colorectal cancer [44]. A phase II trial in melanoma is ongoing and preliminary results described minimal toxicity with tumor responses [45]. LYMPHANGIOGENESIS AND MELANOMA The growth of lymphatic vessels, lymphangiogenesis, received considerable attention in the last two years, due to the identification of proteins specifically expressed on

n tio

The metastatic spread of tumor cells is underlying cause of most cancer-related deaths and both clinical and pathological evidence confirm that the metastatic spread of tumors via lymphatic vessels to local/regional lymph nodes is an early event in metastatic disease, for many solid human tumors. In particular, the use of sentinel lymph nodes has been developed as a promising method for the diagnosis and staging of such diseases as breast cancer and melanoma [70]. An interesting open question is how tumor-associated lymphangiogenesis is regulated and whether tumor-associated lymphatic could be formed by direct vessel co-option, by sprouting and/or splitting from pre-existing lymphatic vessels in surrounding tissues or by recruitment of lymphatic endothelial cells progenitors from bone marrow. Tumor cells or emboli have to overcome a series of barriers to establish metastasis in distant organ. Multiple molecular and cellular responses initiated by a combination of various stimuli may be required for the metastatic event. These sequential processes are thought to include induction of angiogenesis

New Perspectives in the Treatment of Melanoma

Recent Patents on Anti-Cancer Drug Discovery, 2007, Vol. 2, No. 1

75

n tio

u rib

t s i D r

Fig. (1). VEGFs and their receptors. VEGFR-1 (Flt-1) and VEGFR-2 (KDR) have seven extracellular immunoglobulin homology domains, but in VEGFR-3 (Flt-4), the fifth immunoglobulin domain is cleaved on receptor processing into disulfide-linked subunits. VEGFR-1 and VEGFR-2 mediate angiogenesis, whereas VEGFR-3 is involved mainly in lymphangiogenesis.

o F t o N

and/or lymphangiogenesis, detachment from surrounding tumor cell mass and access to blood or lymphatic vessels, survival in the circulation, random or specific arrest in the microvasculature of target organs, exit from the vessels and growth and invasion into the organs to form a metastatic focus. Since lymphatic vessels have a discontinuous basement membrane and lack of tight intraendothelial junctions [71], it is believed that it would be easier for tumor cells to enter into the lymphatic vessels rather than the blood circulation. However the importance of tumor-induced lymphangiogenesis for the spread of lymphatic melanoma is unclear. Recent experimental and clinical evidence strongly suggest that active lymphan-giogenesis is induced by tumor types, including cutaneous melanoma, and that it plays an important role in lymphatic tumor dissemination [72]. The extent of tumor-associated lymphangiogenesis can serve as a powerful prognostic tool for the evaluation of primary cutaneous melanomas. Thereby a better understanding of the lymphatic system may provide new insight into the biology of tumor metastasis as well as novel prognostic and therapeutic tools in metastatic disease. Transgenic mice overexpressing VEGF-C or xenotran-plantation of VEGF-C expressing tumor cells into immuno-deficient mice have demonstrated a role for VEGF-C in tumor lymphangiogenesis and the subsequent formation of lymph node

metastasis [73]. However, there is at present little evidence for lymphangiogenesis in human tumors, which is at variance with the data obtained in animal’s models. Nonetheless, the striking correlation between levels of VEGF-C in primary tumors and lymph node metastasis exists. This suggests that VEGF-C may activate pre-existing lymphatics which then become actively involved in tumor cell chemotaxis, intralymphatic intravasation and distal dissemination. The role of VEGF-C in human tumor metastasis is therefore likely to involve lymphoangiogensis as well as its capacity to induce activation of pre-existing lymphatic endothelium. Interestingly, overexpression of VEGFR-3-Ig by stable transfection of a human lung cancer cell line selected for a highly metastatic phenotype expressing high levels of endogenous VEGF-C was demonstrated to inhibit tumor lymphangiogenesis and lymph nodes metastasis when the cells were grown as tumors in immunodeficient mice [74,75]. On the other hand, preexisting lymphatics were not affected by the VEGFR-3-Ig treatment, suggesting that newly formation vessels are necessary for lymphatic metastasis [76]. VEGF-D expression was shown to be up-regulated in human melanomas compared with melanocytes [76]. The incidence of intratumoral lymphatics (LYVE positive) was significantly higher in metastatic melanomas and correlated with poor-disease-free

76

Recent Patents on Anti-Cancer Drug Discovery, 2007, Vol. 2, No. 1

survival [76]. Many questions remain, however, to be addressed. Firstly, is to study how tumor-associated lymphangiogenesis is regulated. Tumor-associated lymphatics could be formed by direct vessels co-option, by sprouting and/or splitting from pre-existing lymphatic vessels in surrounding tissues or by recruitment of lymphatic endothelial cells (LEC) progenitors from bone marrow. The existence of LEC progenitors has been suggested in avian embryogenesis [77]. VEGFR-3+/CD34+ endothelial precursors have also recently been identified from human foetal liver and blood and upon culture they were shown to express both vascular and lymphatic EC markers [78]. Considering that the lymphatic vessels have a discontinuous basement membrane and lack tight intraendothelial junctions, it is believed that it would be easier for tumor cells to enter the lymphatic vessels rather than the blood circulation lymphatic onces. Experimental evidences have been obtained suggesting that LECs could attract tumor cells by secreting chemokines and therefore actively promote lymphatic metastasis. Secondary lymphoid chemokine (CCL21) is highly expressed in lymph nodes specifically in endothelial cells of high endothelial venules and T cell-rich areas and also in the lymphatic endothelium of multiple organs [79]. CCL21 has been shown to be chemotactic for naïve T cells and it is implicated in T lymphocyte homing and in the migration of antigen-stimulated dendritic cells into secondary lymphoid organs [79]. It has been shown recently that CCR7 and CXCR4 receptors of CCL21 and CXCL12 respectively are highly expressed in human breast cancer cells. Their ligands exhibit peak levels of expression in regional lymph nodes, bone marrow, lung and liver which represent the first destinations of breast cancer metastasis [80]. Furthermore the overexpression of CCR7 by B16 murine melanoma cells enhanced the incidence of lymph node but not lung metastasis when the tumor cells were implanted into the footpads of mice. CCR7 mediated increase of lymphatic metastasis was also shown to be completely suppressed by treatment with neutralizing anti-SLC antibodies [81].

Facchetti et al.

lymphatic endothelium and VEGF-C induces proliferation migration and invasion [87-89]. CURRENT & FUTURE DEVELOPMENTS Melanoma represents a significant and growing public health burden worldwide. However, single-agent chemotherapy or immunotherapy remains the treatment of election choice when systemic therapy is offered. Malignant melanoma of the skin is distinguished by their propensity for early metastatic spread by way of lymphatic vessels to regional lymph nodes. we think that the topic of the present review, in which are discussed the new acknowledgments regarding to the role of lymph-angiogenesis and of angiogenesis in cutaneous melanoma and the possible use of these discoveries in prognostic and therapeutic tools in melanoma metastasis, have important implications for the prognosis and the treatment of human melanomas in the near future. REFERENCES [1]

[2]

u rib

t s i D r

o F t o N

PERSPECTIVES IN THERAPEUTIC LATION OF LYMPHANGIOGENESIS

MANIPU-

Potential inhibitors of the VEGFR-3 include mAbs that block the binding of VEGF-C and VEGF-D to VEGFR-3. A neutralising VEGF-D mAb that blocks binding to both VEGFR-2 and VEGFR-3 was demonstrated to inhibit angiogenesis, lymphangiogenesis and metastatic spread via the lymphatics in a mouse tumor model that secreted recombinant VEGF-D [82]. Another approach would be to sequester VEGF-C and VEGF-D with a soluble version of the extracellular domain of VEGFR-3 [83]. An attracting approach for inhibiting VEGFR-3 signalling pathway would involve identification of orally active small molecules that interfere with the binding of VEGF-C/D to this receptor [84]. Small molecule inhibitors of the tyrosine kinase catalytic domain of VEGFR-3 could be useful for blocking this signalling pathway, showing promise anti-angiogenic effect [85, 86]. Recently inhibitors of the VEGFR-3 signalling pathway may be useful anti-cancer therapeutics via mechanisms other than blocking lymphangiogenesis. For example, Kaposi’s sarcoma is characterized by the presence of a core of spindle-shaped cells that may be derived from

[3] [4] [5]

[6] [7]

[8]

[9]

[10]

[11]

[12] [13] [14] [15]

n tio

de Vries E, Bray FI, Coebergh JW, Parkin DM. Changing epidemiology of malignant cutaneous melanoma in Europe 19531997: rising trends in incidence and mortality but recent stabilizations in western Europe and decreases in Scandinavia. In J Cancer 2003; 107: 119-26. MacKie RM, Bray CA, Hole DJ et al. Incidence of and survival from malignant melanoma in Scotland: an epidemiological study. Lancet 2002; 360: 587-91. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003; 53: 5-26. Giles D, Dwyer T, Coates M, et al. Trends in skin cancer in Australia: An overview of the available data. Trans. Menzies Found 1989; 40: 143-47. Morton DL, Essner R, Calch C. Surgical excision of distant metastasis. In: Bach C, Houghton A, Sober A, et al., Editors Cutaneous melanoma 4th ed. St Louis (MO): Quality Medical Publishing, 2003; 547-72. Balch CM, Buzaid AC, Soong S-J, et al. Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma. J Clin Oncol 2001; 19: 3635-48. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18: 158-66. Millward MJ, Bedikian AY, Conry RM, Gore ME, Pehamberger HE, Sterry W, et al . Randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM): analysis of long term survival. Proc Am Soc Clin Oncol 2004; 23:708 (Abstr. 7505). Luikart SD, Kennealey GT, Kirkwood JM. Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammineplatinum versus dacarbazine in malignant melanoma. J Clin Oncol 1984; 2: 164-68. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17: 2745-51. Middleton M, Lorigan P, Owen J, et al. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 2000; 82: 1158-62. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29(6 Suppl 16): 15-18. Mihm MC Jr, Clark WH Jr, Reed RJ. The clinical diagnosis of malignant melanoma. Semin Oncol 1975; 2: 105-18. Warren BA, Shubik P. The growth of the blood supply to melanoma transplants in the hamster cheek pouch. Lab Invest 1966; 15: 464-78.

New Perspectives in the Treatment of Melanoma [16] [17]

[18] [19] [20] [21] [22] [23]

[24]

[25]

[26] [27]

[28]

Recent Patents on Anti-Cancer Drug Discovery, 2007, Vol. 2, No. 1

Hubler WR Jr., Wolf JE Jr. Melanoma. Tumor angiogenesis and human neoplasia. Cancer 1976; 38: 187-92. Stenzinger W, Bruggen J, Macher E, Sorg C. Tumor angiogenic activity (TAA) production in vitro and growth in the nude mouse by human malignant melanoma. Eur J Cancer Clin Oncol 1983; 19: 649-56. Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene 2003; 22: 3172-79. Weninger W, Uthman A, Pammer J, et al . Vascular endothelial growth factor production in normal epidermis and in benign and malignant epithelial skin tumors. Lab Invest 1996; 75: 647-57. Hawighorst T, Velasco P, Streit M, et al. Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J 2001; 20:2631-40. Hawighorst T. Angiogenesis, lymphangiogenesis, and tumor progression. Zentralbl Gynakol 2002; 124: 497-05. Detmar M, Hirakawa S. The formation of lymphatic vessels and its importance in the setting of malignancy. J Exp Med 2002; 196: 713-18. Oliver G, Detmar M. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev 2002; 16: 77383. Jendreyko N, Popkov M, Rader C, Barbas CF 3rd. Phenotypic knockout of VEGF-R2 and Tie-2 with an intradiabody reduces tumor growth and angiogenesis in vivo. Proc Natl Acad Sci USA 2005; 102: 8293-98. La Porta, R. Comolli. Different levels of TGFbeta, IL-10, IFNgamma and gelatinase A occur in experimental white and black metastases induced by bryostatin 1 or by phorbol estertreated BL6T murine melanoma cells. Clin Exp Metastasis 2000; 18: 361-69. Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155: 739-52. Hendrix MJ, Seftor RE, Seftor EA, et al. Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res 2002; 62: 665-68. Seftor RE, Seftor EA, Koshikawa N, et al. Cooperative interactions of laminin 5 gamma2 chain, matrix metallopro-teinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res 2001; 61: 6322-27. Erhard H, Rietveld FJ, van Altena MC, Brocker EB, Ruiter DJ, de Waal RM. Transition of horizontal to vertical growth phase melanoma is accompanied by induction of vascular endothelial growth factor expression and angiogenesis. Melanoma Res 1997; Suppl 2:S19-26. Marcoval J, Moreno A, Graells J, et al. Angiogenesis and malignant melanoma. Angiogenesis is related to the development of vertical (tumorigenic) growth phase. J Cutan Pathol 1997; 24: 212-18. Salven P, Heikkila P, Joensuu H. Enhanced expression of vascular endothelial growth factor in metastatic melanoma. Br J Cancer 1997; 76: 930-34. Vlaykova T, Laurila P, Muhonen T, et al. Prognostic value of tumour vascularity in metastatic melanoma and association of blood vessel density with vascular endothelial growth factor expression. Melanoma Res 1999; 9: 59-68. Reed JA, McNutt NS, Albino AP. Differential expression of basic fibroblast growth factor (bFGF) in melanocytic lesions demonstrated by in situ hybridization. Implications for tumor progression. Am J Pathol 1994; 144: 329-36. Ugurel S, Rappl G, Tilgen W, Reinhold U. Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 2001; 19: 577-83. Eisen T, Boshoff C, Mak I, et al. Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 2000; 82: 812-17. D’Amato, R.: US20016235756 (2001). Danson S, Lorigan P, Arance A, et al. Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma. J Clin Oncol 2003; 21: 2551-57.

[30]

[31] [32]

[33]

[34]

[35] *[36] [37]

[39] [40]

[41] *[42] [43]

[44] [45]

[46] [47]

Hwu WJ, Krown SE, Menell JH, et al. Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J Clin Oncol 2003; 21: 3351-56. Dredge K, Marriott JB, Macdonald CD, et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002; 87: 1166-72. Bartlett JB, Michael A, Clarke IA, et al. Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers. Br J Cancer 2004; 90: 955-61. Tucker GC. Alpha v integrin inhibitors and cancer therapy. Curr Opin Investig Drugs 2003; 4: 722-31. Fanslow, W.C., Cerretti, D.P., Poindexter, K.M., Black, R.A.: US20067074408 (2006). Peterson AC, Swiger S, Stadler W, et al. Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in patients with advanced melanoma. Proc Am Soc Clin Oncol 2003; 22: 712 (Abstr. 2863). Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335-42. Carson WE, Biber J, Shah N, et al. A phase 2 trial of a recombinant humanized monoclonal anti-vascular endothelial growth factor (VEGF) antibody in patients with malignant melanoma Proc Am Soc Clin Oncol 2003; 22: 715 (Abstr. 2873). Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997; 276: 1423-25. Achen MG, Jeltsch M, Kukk E, et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Sci Acad USA 1998; 95: 548-53. Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001; 20: 672-82. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7: 192-98. Veikkola T, Jussila L, Makinen T, et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 2001; 20: 1223-31. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001; 7: 186-91. Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 67174. Sleeman JP, Krishnan J, Kirkin V, et al. Markers for the lymphatic endothelium: in search of the holy grail? Microsc Res Tech 2001; 55: 61-69. Kaipainen A, Korhonen J, Mustonen T, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 1995; 92: 3566-70. Kukk E, Lymboussaki A, Taira S, et al. VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 1996; 122: 3829-37. Oh SJ, Jeltsch MM, Birkenhager R, et al . VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 1997; 188: 96-109. Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 1996; 15: 290-98. Banerji S, Ni J, Wang SX, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999; 144: 789-801. Prevo R, Banerji S, Ferguson DJP, Clasper S, Jackson DG. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 2001; 276: 19420-30. Jackson DG, Prevo R, Clasper S, Banerji S. LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol 2001; 22: 317-21.

[48] [49] [50] [51] [52] [53] [54]

[55]

[56]

[57]

[58] [59] [60]

n tio

u rib

t s i D r

o F t o N [29]

[38]

77

78

Recent Patents on Anti-Cancer Drug Discovery, 2007, Vol. 2, No. 1

[61] [62] [63] [64]

[65] [66] [67] [68] [69] [70] [71] [72] [73]

[74]

Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell 1999; 98: 769-78. Sosa-Pineda B, Wigle JT, Oliver G. Hepatocyte migration during liver development requires Prox1. Nat Genet 2000; 25: 254-55. Wigle JT, Chowdhury K, Gruss P, Oliver G. Prox1 function is crucial for mouse lens-fibre elongation. Nat Genet 1999; 21: 31822. Weninger W, Partanen TA, Breiteneder-Geleff S, et al. Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests a lymphatic endothelial cell origin of Kaposi's sarcoma tumor cells. Lab Invest 1999; 79: 243-51. Ebata N, Nodasaka Y, Sawa Y, et al. Desmoplakin as a specific marker of lymphatic vessels. Microvasc Res 2001; 61: 40-48. Wells KE, Rapaport DP, Cruse CW, et al. Sentinel lymph node biopsy in melanoma of the head and neck. Plast Reconstr Surg 1997; 100: 591-94. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818-22. Albertini JJ, Cruse CW, Rapaport D, et al. Intraoperative radiolympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 1996; 223: 217-24. Leak LV. The structure of lymphatic capillaries in lymph formation. Fed Proc 1976; 35: 1863-71. Dadras SS, Detmar M. Angiogenesis and lymphangiogenesis of skin cancers. Hematol Oncol Clin North Am 2004; 18: 1059-70. Tille JC, Nisato R, Pepper MS. Lymphangiogenesis and tumor metastasis. Novartis Found Symp 2004; 256: 112-31. Karpanen T, Egeblad M, Karkkainen MJ, et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001; 61: 1786-90. He Y, Kosaki K, Karpanen T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 2002; 94: 819-25. Krishnan J, Kirkin V, Steffen A, et al. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res 2003; 63: 71322. Achen MG, Williams RA, Minekus MP, et al. Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumor angiogenesis. J Pathol 2001; 193: 14754. Dadras SS, Paul T, Bertoncini J, et al. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 2003; 162: 1951-60.

[76]

[77] [78] [79]

[80] [81]

[82] [83] [84]

[85]

[86]

Schneider M, Othman-Hassan K, Christ B, Wilting J. Lymphangioblasts in the avian wing bud. Dev Dyn 1999; 216: 311-19. Salven P, Mustjoki S, Alitalo R, Alitalo K, Rafii S. VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood 2003; 101: 168-72. Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci USA 1998; 95: 258-63. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50-56. Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST. Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 2001; 93: 1638-43. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001; 7: 186-91. Makinen T, Jussila L, Veikkola T, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 2001; 7: 199-205. Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, deVos AM. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 1997; 91: 695704. Fong AT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999; 59: 99-106. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000; 60: 2178-89. Skobe M, Brown LF, Tognazzi K, et al. Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and Flt-4 are expressed in AIDS-associated Kaposi's sarcoma. J Invest Dermatol 1999; 113: 1047-53. Marchiò S, Primo L, Pagano M, et al. Vascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi's sarcoma cells. J Biol Chem 1999; 274: 27617-22. Skobe M, Brown LF, Tognazzi K, et al. Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and Flt-4 are expressed in AIDS-associated Kaposi's sarcoma. J Invest Dermatol 1999; 113: 1047-53.

[87]

[88] [89]

n tio

u rib

t s i D r

o F t o N [75]

Facchetti et al.

New Perspectives in the Treatment of Melanoma: Anti ...

toxicity resulting in increased numbers of hospital admis- sions. Immunotherapy continues to be evaluated in metas- tatic disease such as interferon (IFN)-alpha ...

253KB Sizes 0 Downloads 186 Views

Recommend Documents

Drug Resistance in Melanoma: New Perspectives
E-mail: [email protected]. Cancer chemotherapy efficacy is frequently ..... regulation in the tumor bulk. However, the major barrier to the therapy is the ...

Drug Resistance in Melanoma: New Perspectives
the U.S. Food and Drug Administration (FDA) for the treat- ment of metastatic ... dent that the complex physiological network of ABC trans- porters has a pivotal role in host .... (XAF1) has been identified using two hybrid system [67]. XAF1 was ....

Perspectives in the new Russulales
recently elucidated by molecular sequence data in the homobasidiomycetes. The order is ... sake of brevity in this volume we direct the reader to those citations. .... the rosettes begins at the center of the pileus trama before the hymenium is ...

Perspectives on the Historical Treatment of People with ...
1800: Science begins to replace religion as the main authority guiding leaders in the. West. Biology and science are used to .... The group organizes sit-ins, picket lines, and demonstrations, and it travels to Washington, D.C., ..... cially needy pe

New-Perspectives-In-Magnetism-Of-Metals.pdf
Whoops! There was a problem loading more pages. Whoops! There was a problem previewing this document. Retrying... Download. Connect more apps.

Melanoma Staging.pdf
Retrying... Download. Connect more apps... Try one of the apps below to open or edit this item. Melanoma Staging.pdf. Melanoma Staging.pdf. Open. Extract.

Sentinel-Node Biopsy in Melanoma
Sep 28, 2006 - The most notable of the prior studies was the analysis of the American Joint Committee on. Cancer's melanoma database of more than 16,000 patients, which led to ... With respect to control of regional disease, patients in the observati

Surgical Management of Melanoma-In-Situ Using a ... - Springer Link
Dec 3, 2008 - 1Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive,. SRB 24016, Tampa, FL 33612, USA; 2Department of Surgery, University of South Florida College of Medicine, Tampa,. FL, USA; 3D

Malignant Melanoma in the 21st Century, Part 2
†Micrometastases are diagnosed after elective or sentinel lymphadenectomy. ‡Macrometastases ...... although a trend toward prolonged survival was reported.

Synthesis and anti-microbial / anti-malarial activity of a new ... - Arkivoc
antiparkinson,12 antidepressant,13 analgesic,14 diuretic15,16 and antihistamine ... MHz, DMSO-d6) spectrum of the compound 11a showed ten signals ...

Current surgical management of melanoma
an insignificant difference in the local recurrence rate between the two groups ..... We believe that it is in the patient's best interest to be fully informed as to the ...

New Editor at Perspectives in Biology and Medicine - Johns Hopkins ...
Apr 9, 2014 - A literature scholar with degrees from Cornell College and the University ... “We thank the authors who have contributed over the years to make ...

DETERMINATION OF THE PERFORMANCE OF ANDROID ANTI ...
OF ANDROID ANTI-MALWARE SCANNERS. AV-TEST GmbH. Klewitzstr. 7 ..... Families with less than 10 samples are classified as 'Other'. The total sample set.

pdf-1329\new-perspectives-in-mathematical-biology-fields-institute ...
... of the apps below to open or edit this item. pdf-1329\new-perspectives-in-mathematical-biology-fields-institute-communications-by-siv-sivaloganathan.pdf.