Current Clinical and Research Approaches to Optimizing Regional Chemotherapy: Novel Strategies Generated Through a Better Understanding of Drug Pharmacokinetics, Drug Resistance, and the Development of Clinically Relevant Animal Models

Surgical Oncology Clinics of North America

Volumn 17, Issue 4, 2008, Pages 731-758

  Beasley, Georgia M ^a   Kahn, Lauren ^a   Tyler, Douglas S ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 O BENZYLGUANINE; ADH 1; ALKYLATING AGENT; BUTATHIONE SULFOXIME; CARBOPLATIN; CHLORMETHINE; CISPLATIN; DACARBAZINE; DACTINOMYCIN; DASATINIB; DOXORUBICIN; FOTEMUSTINE; GLYCOPROTEIN P; HISTAMINE; HYPOXIA INDUCIBLE FACTOR 1; INTERFERON; INTERLEUKIN 2; LUNG RESISTANCE PROTEIN; MELPHALAN; MULTIDRUG RESISTANCE PROTEIN 1; NERVE CELL ADHESION MOLECULE; OXIME DERIVATIVE; PACLITAXEL; PENTAPEPTIDE; PROTEIN TYROSINE KINASE; SORAFENIB; STAT3 PROTEIN; TEMOZOLOMIDE; TUMOR NECROSIS FACTOR; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTINEOPLASTIC ACTIVITY; CALCULATION; CANCER CHEMOTHERAPY; CANCER INCIDENCE; CANCER SURVIVAL; CLINICAL TRIAL; DISEASE MODEL; DNA ADDUCT; DRUG BLOOD LEVEL; DRUG DELIVERY SYSTEM; DRUG DISTRIBUTION; DRUG EFFECT; DRUG EFFICACY; DRUG HALF LIFE; DRUG INACTIVATION; DRUG INFUSION; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG RESPONSE; HUMAN; HYPERTHERMIC ISOLATED LIMB PERFUSION; HYPERTHERMIC THERAPY; IN-TRANSIT METASTASIS; ISOLATED LIMB INFUSION; MATHEMATICAL ANALYSIS; MELANOMA; NEUROPATHY; NEUROTOXICITY; NONHUMAN; REGIONAL CANCER CHEMOTHERAPY; REVIEW; RHABDOMYOLYSIS; UNSPECIFIED SIDE EFFECT;

ANIMALS; ANTINEOPLASTIC AGENTS; CHEMOTHERAPY, CANCER, REGIONAL PERFUSION; DISEASE MODELS, ANIMAL; DRUG RESISTANCE, NEOPLASM; HUMANS; HYPERTHERMIA, INDUCED; NEOPLASMS;

EID: 49649107394     PISSN: 10553207     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.soc.2008.04.002     Document Type: Review

References (107)

1. Jemel A., Murray T., Samuels A., et al. Cancer statistics 2003. CA Cancer J Clin 53 (2003) 5-26
2. Balch C.M., Houghton A.N., and Peters L.J. Cutaneous melanoma. In: DeVita V.T., Hellman S., and Rosenberg S.A. (Eds). Cancer: principles and practice of oncology. 4th edition (1993), JB Lippincott, Philadelphia 1612-1661
3. Pawlik T.W., Ross M.I., Johnson M.M., et al. Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy. Ann Surg Oncol 11 (2004) S61
4. Jaques D.P., Coit D.G., and Brennan M.F. Major amputation for advanced malignant melanoma. Surg Gynecol Obstet 169 (1989) 1-6
5. Ebskov L.B. Major amputation in melanoma: an epidemiological study. J Surg Oncol 52 (1993) 89-91
6. Kourtesis G.J., McCarthy W.H., and Milton G.W. Major amputations for melanoma. Aust N Z J Surg 53 (1983) 241-244
7. Flaherty K.T., Brose M., Schuchter L., et al. Phase I/II trial of Bay 43-9006, carboplatin and paclitaxel demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. Proc Am Soc Clin Oncol 22 14S (2004) 7507
8. Hochster H., Strawderman M.H., Harris J.E., et al. Conventional dose melphalan is inactive in metastatic melanoma: results of an Eastern Cooperative Oncology Group Study. Anticancer Drugs 10 2 (1999) 245-248
9. Creech O., Krementz E.T., Ryan R.F., et al. Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann Surg 148 (1958) 616-632
10. Stehlin J.S. Hyperthermic perfusion with chemotherapy for cancers of the extremity. Surg Gynecol Obstet 129 (1969) 305-308
11. Benckhuijsen C., Kroon B.B.R., van Geel A.N., et al. Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol 14 (1988) 157-163
12. Fletcher W.S., Pommier R., and Small K. Results of cisplatin hyperthermic isolation perfusion for stage IIIA and IIIAB extremity melanoma. Melanoma Res 4 Suppl 1 (2004) 17-19
13. Hoekstra H.J., Schraffordt Koops H., de Vries L.G., et al. Toxicity of hyperthermic isolated limb perfusion with cisplatin for recurrent melanoma of the lower extremity after previous perfusion treatment. Cancer 72 4 (1993) 1224-1229
14. Krementz E.T., and Ryan R.F. Chemotherapy of melanoma of the extremities by perfusion: fourteen-years clinical experience. Ann Surg 175 (1972) 900-917
15. Thompson J.F., and Gianoutsos M.P. Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J Surg 16 (1992) 227-233
16. Bonenkamp J.J., Thompson J.F., Wilt J.H., et al. Isolated limb infusion with fotemustine after dacarbazine chemosensitisation for inoperable loco-regional melanoma recurrence. Eur J Surg Oncol 30 (2004) 1107-1112
17. Lejeune F.J., and Ghanem G.E. A simple and accurate new method for cytostatic dosimetry in isolation perfusion of the limbs based on exchangeable blood volume determination. Cancer Res 47 (1987) 639-643
18. Briele H.A., Djuric M., Jung D.T., et al. Pharmacokinetics of melphalan in clinical isolation perfusion of the extremities. Cancer Res 45 (1985) 1885-1889
19. Di Filippo F., Calabro A., Giannarelli D., et al. Prognostic variables in recurrent limb melanoma treated with hyperthermic antiblastic perfusion. Cancer 63 (1989) 2551-2561
20. Klaase J.M., Kroon B.B.R., van Geel A.N., et al. Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan. Surgery 115 (1994) 39-45
21. Kroon B.R., van Geel A.N., Benckhuijsen C., et al. Normothermic isolation perfusion with melphalan for advanced melanoma of the limbs. Anticancer Res 7 (1987) 441-442
22. Minor D.R., Allen R.E., Alberts D., et al. A clinical and pharmacokinetic study of isolated limb perfusion with heat and melphalan for melanoma. Cancer 55 (1985) 2638-2644
23. Skene A.L., Bulman A.S., Williams T.F., et al. Hyperthermic isolated limb perfusion with melphalan in the treatment of advanced malignant melanoma of the lower limb. Br J Surg 77 (1990) 765-767
24. Storm F.K., and Morton D.L. Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity. Am J Surg 15 (1985) 32-35
25. Aloia T.A., Grubbs E., Onaitis M., et al. Predictors of outcome after hyperthermic limb perfusion: role of tumor response. Arch Surg 140 11 (2005) 1115-1120
26. Taber S.W., and Polk Jr. H.C. Mortality, major amputation rates, and leukopenia after isolated limb perfusion with phenylalanine mustard for the treatment of melanoma. Ann Surg Oncol 4 (1997) 440-445
27. Vrouenraets B.C., Klaase J.M., Nieweg O.E., et al. Toxicity and morbidity of isolated limb perfusion. Semin Surg Oncol 14 (1998) 224-231
28. Fraker D.L., Alexader H.R., Ross M., et al. A phase III trial of isolated limb infusion perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNF-α) plus interferon-gamma (IFN). Ann Surg Oncol 9 (2002) S8
29. Lienard D., Lejeune F., Delmotte J., et al. High doses of rTNFα in combination with IFN-gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 10 (1992) 52-60
30. Lienard D., Lejeune F., and Ewalenko I. In transit metastases of malignant melanoma treated by high doses of TNFα in combination with interferon-gamma and melphalan in isolation perfusion. World J Surg 16 (1992) 234-240
31. Cornett W.R., McCall L.M., Petersen R.P., et al. Prospective randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone versus melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 24 (2006) 4196-4201
32. Lindner P., Doubrovsky A., Kam P.C.A., et al. Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol 9 (2002) 127-136
33. Zager J.S., Gershenwald J.E., Aldrink J., et al. Isolated limb infusion for locally recurrent and in-transit extremity melanoma: a combined institutional initial experience. Presented at Society of Surgical Oncology 59th annual cancer symposium. San Diego, CA March 23-26 (2006)
34. Clark J., Grabs A.J., Parsons P.G., et al. Melphalan uptake, hyperthermic synergism and drug resistance in a human cell culture model for the isolated limb perfusion of melanoma. Melanoma Res 4 (1994) 365-370
35. Honess D.J., Donaldson J., Workman P., et al. The effect of systemic hyperthermia on melphalan pharmacokinetics in mice. Br J Cancer 51 (1985) 77-84
36. Laskowitz D.T., Elion G.B., Dewhirst M.W., et al. Hyperthermia-induced enhancement of melphalan activity against a melphalan-resistant human rhabdomyosarcoma xenograft. Radiat Res 129 (1992) 218-223
37. Song C.W. Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Res 44 Suppl (1984) 4721s-4730s
38. Urano M., and Ling C.C. Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro. Int J Hyperthermia 18 4 (2002) 307-315
39. Hettinga J.V., Lemstra W., Meijer C., et al. Mechanism of hyperthermic potentiation of cisplatin action in cisplatin-sensitive and -resistant tumour cells. Br J Cancer 75 (1997) 1735-1763
40. Fernandes R.S., and Cotter T.G. Apoptosis or necrosis: intracellular levels of glutathione influence mode of cell death. Biochem Pharmacol 48 (1994) 675-681
41. Hildebrandt B., Wust P., and Ahlers O. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 43 (2002) 33-56
42. Harmon B.V., Takano Y.S., Winterford C.M., et al. The role of apoptosis in the response of cells and tumours to mild hyperthermia. Int J Radiat Biol 59 (1991) 489-501
43. Sekiguchi I., Suzuki M., Shinomiya M., et al. Effects of cisplatin on cell cycle kinetics, morphological change, and cleavage pattern of DNA in two human ovarian carcinoma cell lines. Oncology 53 (1996) 19-26
44. Sakaguchi Y., Stephen L.C., Makino M., et al. Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats. Cancer Res 55 (1995) 5459-5464
45. Ohnishi K., and Ohnishi T. Heat-induced p53-dependent signal transduction and its role in hyperthermic cancer therapy. Int J Hyperthermia 17 (2001) 415-427
46. Parsons P.G., Carter F.B., Morrison L., et al. Mechanism of melphalan resistance development in human melanoma cell lines. Cancer Res 41 (1981) 1525-1534
47. Kroon B.B. Regional isolated perfusion in melanoma of the limbs: accomplishments, unsolved problems, future. Eur J Surg Oncol 14 (1988) 101-110
48. Wu Z.Y., Smithers B.M., and Roberts M.S. Melphalan dosing regimens for management of recurrent melanoma by isolated limb perfusion: application of a physiological pharmacokinetic model based on melphalan distribution in the isolated perfused rat hindlimb. Melanoma Res 7 3 (1997) 252-264
49. Boddie A.W., Briele H., Krementz E., et al. A phase I study of melphalan in 40 C isolated limb perfusion using packed red blood cells and lactated Ringer's perfusate. Proc Am Soc Clin Oncol 11 (1992) 351
50. Wieberdink J., Benckhuijsen C., and Braat R.P. Dosimetry in isolated perfusion of the limbs by assessment of perfused tissue and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 18 (1982) 905-910
51. Tyler D.S., Yashimoto Y., Grubbs E., et al. Novel strategies to overcome chemoresistance in regional melanoma therapy by systemic modulation of tumor proteins. Melanoma Res 16 Suppl 1 (2006) S100
52. Roberts M.S., Wu Z.Y., Siebert G.A., et al. Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy. Melanoma Res 11 4 (2001) 423-431
53. Thompson J.F., Ramzan I., Kam P.C.A., et al. Clinical pharmacokinetics of melphalan during isolated limb perfusion: compartmental modeling and moment analysis. Reg Cancer Treat 8 (1995) 83-87
54. Brady M.S., Brown K., Patel A., et al. A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity. Ann Surg Oncol 13 8 (2006) 1123-1129
55. Thompson J.F., Ramzan I., Kam P.C.A., et al. Pharmacokinetics of melphalan in isolated limb infusion for melanoma. Reg Cancer Treat 9 (1996) 13
56. Siemann D.W., Chapman M., and Biekirch A. Effects of oxygenation and pH on tumor cell response to alkylating chemotherapy. Int J Radiat Oncol Biol Phys 20 (1991) 287-289
57. Cheng T.-Y., Grubbs E., Abdul-Wahab O., et al. Marked variability of melphalan plasma drug levels during regional hyperthermic isolated limb perfusion. Am J Surg 186 5 (2003) 460-467
58. Scott R.N., Blackie R., Kerr D.J., et al. Melphalan concentration and distribution in the tissues of tumour-bearing limbs treated by isolated limb perfusion. Eur J Cancer 11 (1992) 1811-1813
59. Wu Z.Y., Smithers B.M., Anderson C., et al. Can tissue drug concentrations be monitored by microdialysis during or after isolated limb perfusion for melanoma treatment?. Melanoma Res 10 (2000) 47-54
60. Thompson J.F., Anisimov Y.G., Smithers B.M., et al. Microdialysis and response during regional chemotherapy by isolated limb infusion of melphalan for limb malignancies. Br J Cancer 85 2 (2001) 157-165
61. Thompson J.F., Hunt J.A., Shannon K.F., et al. Frequency and duration of remission after isolated limb perfusion for melanoma. Arch Surg 132 (1997) 903-907
62. Manusma E.R., Nooijen P.T., Stavast J., et al. Synergistic antitumour effect or recombinant human tumour necrosis factor alpha with melphalan in isolated limb perfusion in the rat. Br J Surg 83 (1996) 551-555
63. McClean S., and Hill B.T. An overview of membrane, cytosolic, and nuclear proteins associated with the expression of resistance to multiple drugs in vitro. Biochim Biophys Acta 1114 (1992) 107-127
64. Lienard D., Eggermont A.M., Schraffordt K.H., et al. Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-α), interferon gamma (IFN-γ) and melphalan for melanoma stage III. Results of a multi-centre pilot study. Melanoma Res 4 Suppl 1 (1994) 21-26
65. Lienard D., Eggermont A.M., Kroon B.B., et al. Isolated limb perfusion in primary and recurrent melanoma: indications and results. Semin Surg Oncol 14 (1998) 202-209
66. Grunhagen D.J., de Wilt J.H., Graveland W.J., et al. Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor-alpha and melphalan for limb-threatening soft tissue sarcoma. Cancer 106 8 (2006) 1776-1784
67. Eggermont A.M., Schraffordt Koops H., Lienard D., et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 6 (1996) 756-764 [discussion: 764-5]
68. Pennacchioli E., Deraco M., Mariani L., et al. Advanced extremity soft tissue sarcoma: prognostic effect of isolated limb perfusion in a series of 88 patients treated at a single institution. Ann Surg Oncol 14 2 (2007) 553-599
69. Harada N., Nagasaki A., Hata H., et al. Down-regulation of CD98 in melphalan-resistant myeloma cells with reduced drug uptake. Acta Haematol 103 (2001) 144-151
70. van Bladeren P.J. Glutathione conjugation as bioactivation reaction. Chem Biol Interact 129 (2000) 61-76
71. Van Etten B., Van Tiel S.T., Ambagtsheer G., et al. Isolated limb perfusion based anti-p21ras gene therapy in a rat rhabdomyosarcoma. Anticancer Res 24 4 (2004) 2295-2301
72. Suzukake K., Petro B., and Vistica D. Reduction in glutathione content of LPAM resistant cells confers drug sensitivity. Biochem Pharmacol 31 (1982) 121-124
73. Butler B., Clapper M., and Tew K. Glutathione-S-transferase in nitrogen mustard-resistant and -sensitive cell lines. Mol Pharmacol 31 (1987) 575-578
74. Robson C., Lewis A., Wolf C., et al. Reduced levels of drug-induced DNA cross-linking in nitrogen mustard-resistant Chinese hamster ovary cells expressing elevated glutathione-transferase activity. Cancer Res 47 (1987) 6022-6027
75. Green J., Vistica D., Young R., et al. Potentiation of melphalan cytotoxicity in human ovarian cancer cell lines by glutathione depletion. Cancer Res 44 (1984) 5427-5431
76. Suzukake K., Vistica B., and Vistica D. Resistant tumor cells and its relationship to intracellular glutathione content. Biochem Pharmacol 32 (1983) 165-167
77. Grubbs E.G., Abdel-Wahab O., Cheng T.Y., et al. In-transit melanoma: the role of alkylating-agent resistance in regional therapy. J Am Coll Surg 199 3 (2004) 419-427
78. Pu Q., Bianchi P., and Bezwoda W.R. Alkylator resistance in human B lymphoid cell lines: melphalan accumulation, cytotoxicity, interstrand-DNA-crosslinks, cell cycle analysis, and glutathione content in the melphalan-sensitive B-lymphocytic cell line (WIL2) and in the melphalan-resistant B-CLL cell line (WSU-CLL). Anticancer Res 20 (2000) 2561-2568
79. Eder Jr. J.P., Chan V.T., Ng S.W., et al. DNA topoisomerase II alpha expression is associated with alkylating agent resistance. Cancer Res 55 (1995) 6109-6116
80. Spanswick V.J., Craddock C., Sekhar M., et al. Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. Blood 100 1 (2002) 224-229
81. Larrivee B., and Averill D.A. Melphalan resistance and photoaffinity labelling of P-glycoprotein in multidrug-resistant Chinese hamster ovary cells: reversal of resistance by cyclosporin A and hyperthermia. Biochem Pharmacol 58 (1999) 291-302
82. Komdeur R., Plaat B.E., Hoekstra H.J., et al. Expression of P-glycoprotein, multidrug resistance-associated protein 1, and lung resistance-related protein in human soft tissue sarcomas before and after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Cancer 91 10 (2001) 1940-1948
83. Stein U., Jurchott K., Schlafke M., et al. Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients. J Clin Oncol 20 15 (2002) 3282-3292
84. Comerford K.M., Wallace T.J., Karhausen J., et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62 12 (2002) 3387-3394
85. Thews O., Gassner B., Kelleher D.K., et al. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8 2 (2006) 143-152
86. Bauer T., Gutierrez M., Dudrick D., et al. A human melanoma xenograft in a nude rat responds to isolated limb perfusion with TNF plus melphalan?. Surgery 133 4 (2003) 420-428
87. Menon C., Ghartey A., Canter R., et al. Tumor necrosis factor-alpha damages tumor blood vessel integrity by targeting VE-cadherin. Ann Surg 244 5 (2006) 781-791
88. Menon C., Iyer M., Prabakaran I., et al. TNF-alpha downregulates vascular endothelial Flk-1 expression in human melanoma xenograft model. Am J Physiol Heart Circ Physiol 284 1 (2003) H317-H329
89. Kelley S.T., Menon C., Buerk D.G., et al. Acidosis plus melphalan induces nitric oxide-mediated tumor regression in an isolated limb perfusion human melanoma xenograft model. Surgery 132 2 (2002) 252-258
90. Canter R.J., Zhou R., Kesmodel S.B., et al. Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma. Ann Surg Oncol 11 3 (2004) 265-273
91. Eggermont A.M., de Wilt J.H., and ten Hagen T.L. Current uses of isolated limb perfusion in the clinic and a model system for new strategies. [review]. Lancet Oncol 4 7 (2003) 429-437
92. Brunstein F., Rens J., van Tiel S.T., et al. Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery. Br J Cancer 95 12 (2006) 1663-1669
93. Brunstein F., Hoving S., Aan de Wiel-Ambagtsheer G., et al. Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion. Cancer Immunol Immunother 56 4 (2007) 573-580
94. Brunstein F., Hoving S., Seynhaeve A.L., et al. Synergistic antitumor activity of histamine plus melphalan in isolated limb perfusion: preclinical studies. J Natl Cancer Inst 96 21 (2004) 1603-1610
95. Hoving S., Brunstein F., Ann de Wiel-Ambagtsheer G., et al. Synergistic antitumor response of interleukin 2 with melphalan in isolated limb perfusion in soft tissue sarcoma-bearing rats. Cancer Res 65 10 (2005) 4300-4308
96. Ueno T., Ko S.H., Grubbs E., et al. Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine. Mol Cancer Ther 5 3 (2006) 732-738
97. Ko S.H., Ueno T., Yoshimoto Y., et al. Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity. Clin Cancer Res 12 1 (2006) 289-297
98. Grubbs E.G., Ueno T., Abdel-Wahab O., et al. Modulation of resistance to regional chemotherapy in the extremity melanoma model. Surgery 136 2 (2004) 210-218
99. Wu Z., Roberts M.S., Parsons P.G., et al. Isolated limb perfusion with melphalan for human melanoma xenografts in the hindlimb of nude rats: a surviving animal model. Melanoma Res 7 (1997) 19-26
100. Roberts M.S., Wu Z.Y., Siebert G.A., et al. Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat. Melanoma Res 11 6 (2001) 611-618
101. Wu Z.Y., Smithers B.M., and Roberts M.S. Tissue and perfusate pharmacokinetics of melphalan in isolated perfused rat hindlimb. J Pharmacol Exp Ther 282 3 (1997) 1131-1138
102. Smalley K.S.M., and Herlyn M. Targeting intracellular signaling pathways as a novel strategy in melanoma therapeutics. Ann N Y Acad Sci 1059 (2005) 16-24
103. Davies H., Bignell G.R., Cox C., et al. Mutations of the BRAF gene in human cancer. Nature 417 (2002) 949-954
104. Eisen T., Ahmad T., Gore M., et al. Phase 1 trial of Bay 43-9006 (Sorafenib) combined with DTIC in metastatic melanoma patients. Proc Am Soc Clin Oncol 712 (2005) 7508
105. Lorigan P., Corrie P., Chao D., et al. Phase II trial of Sorafenib combined with dacarbazine in metastatic melanoma patients. J Clin Oncol 24 18 Suppl (2006) 8012
106. Niu G., Bowman T., Huang M., et al. Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21 (2002) 7001-7010
107. Niu G., Wright K.L., Huang M., et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21 (2002) 2000-2008