Among the few hundred Ser/Thr kinases a handful are involved in transmitting the signals of upstream PTKs, and their activity is essential for cell proliferation and the onset of anti-apoptotic signaling (Fig. 7). Their abnormal enhanced activities are augmented by the deletion of negative regulators such as protein inhibitors of Cdks and the deletion of the tumor suppressor PTEN, the negative regulator of the PI3' kinase pathway. Thus, the activities of these kinases are enhanced by the synergistic action of the enhanced upstream PTKs combined with the inactivation of downstream negative regulators. As an example, Cdks execute the cell cycle and their activity has been found to be enhanced not only as a result of enhanced upstream signaling but also as a result of the overexpression of cyclin D1 and the deletion of Cdk inhibitors such as p15 and p16. Thus, Cdk2, Cdk1/Cdc2, and Cdk4 have become targets for new antineoplastic agents. Similarly, PI3' kinase signaling has been found to be enhanced by the deletion of its negative regulation PTEN. This deletion, characteristic of high-grade tumors, potentiates the already strong positive regulation of the PI3' kinase/PKB/mTor module complex by PTKs. Because of findings such as these, inhibitors of PKB and mTor are in development as antitumor agents.
Progress toward generation of PKB inhibitors (Aktstatins) has been recently reported . In this study, the PKA inhibitor H-89 was modified to reduce its affinity to PKA but retaining and even improving its affinity to PKB/Akt (Fig. 8). Attempts are currently being made to widen the gap in selectivity towards PKB/Akt and increase the affinity.
Inhibitors of the Ras Pathway: Raf and Mek Inhibitors
Inhibitors of the Ras-Raf-Mek-Erk pathway have great therapeutic potential, as mutated Ras is the hallmark of many cancers. Mutated Ras occurs in 30% of all human tumors, in 80% of pancreatic cancers, in 50% of colorectal cancers, in 40% of lung cancer, and in 20% of hematopoietic malignancies. So far, no real success has been achieved in developing Ras inhibitors, but promising developments are reported in the development of Raf and Mek inhibitors. A recent study  shows that mutations that activate the kinase activity in B-Raf occur in « 66% of human melanomas, suggesting that Raf kinase inhibitors (such as the recently reported Onyx/Bayer compound BAY 43-9006 ) (Fig. 9) may be utilized to treat metastatic melanoma. Mek inhibitors such as PD 184352  are also very promising. PD 184352 (Fig. 9) is a highly potent and selective inhibitor of Mek that is orally active. Tumor growth has been inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor . Efficacy was achieved with a wide range of doses with no signs of toxicity and were correlated with a reduction in the levels of mitogen-activated protein kinase in excised tumors. These data indicate that Mek inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer. It is highly likely that many more inhibitors of this pathway will emerge in years to come.
Figure 9 Cdk, Raf, and Mek inhibitors.
Figure 9 Cdk, Raf, and Mek inhibitors.
Inhibitors of Cdks are being developed as anticancer agents [76-81]. Falvopiridol (Fig. 9) inhibits Cdk4/cyclin D and Cdk1/CyclinB1, with an IC50 value of 200 nM as compared to PKA and PKC, which it inhibits with IC50 of 960 |M and 10 |M, respectively . This inhibitor is currently in clinical development (Table 1) .
Although we have been aware of PKC isozymes for a long time, little progress has been made in utilizing PKC inhibitors as therapeutic agents. Some agents are in development as anticancer drugs [77,84-86]. PKC-P inhibitors are also potential agents against vascular dysfunction  and are being evaluated as agents against vascular retinopa-thy, a complication of diabetes.
Rapamycin, the inhibitor of mTor, is effective as an inhibitor of angiogenesis and therefore is a potential anticancer drug . Rapamycin is also effective in the inhibition of restenosis when applied on coated stents .
1. Levitzki, A. (1994). Signal-transduction therapy. A novel approach to disease management. Eur. J. Biochem. 226, 1-13.
2. Benhar, M., Engelberg, D., and Levitzki, A. (2002). ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep. 3, 420-5.
3. Levitzki, A. (1990). Tyrphostins: potential antiproliferative agents and novel molecular tools. Biochem. Pharmacol. 40, 913-918.
4. Levitzki, A. and Gilon, C. (1991). Tyrphostins as molecular tools and potential antiproliferative drugs. Trends Pharmacol. Sci. 12, 171-174.
5. Levitzki, A., Gazit, A., Osherov, N., Posner, I., and Gilon, C. (1991). Inhibition of protein-tyrosine kinases by tyrphostins. Methods Enzymol. 201, 347-361.
6. Levitzki, A. (1992). Tyrphostins, tyrosine kinase blockers as novel antiproliferative agents and dissectors of signal transduction. FASEB J. 6, 3275-3282.
7. Levitzki, A. (1995). Signal transduction interception as a novel approach to disease management. Ann. N.Y. Acad. Sci. 766, 363-368.
8. Levitzki, A. and Gazit, A. (1995). Tyrosine kinase inhibition, an approach to drug development. Science 267, 1782-8.
9. Levitzki, A. (1996). Targeting signal transduction for disease therapy. Curr. Opin. Cell Biol. 8, 239-244.
10. Strawn, L. M., McMahon, G., App, H., Schreck, R., Kuchler, W. R., Longhi, M. P., Hui, T. H., Tang, C., Levitzki, A., Gazit, A., Chen, I., Keri, G., Orfi, L., Risau, W., Flamme, I., Ullrich, A., Hirth, K. P., and Shawver, L. K. (1996). Flk-1 as a target for tumor growth inhibition. Cancer Res. 56, 3540-3545.
11. Yaish, P., Gazit, A., Gilon, C., and Levitzki, A. (1988). Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242, 933-945.
12. Gazit, A., Yaish, P., Gilon, C., and Levitzki, A. (1989). Tyrphostins I, synthesis and biological activity of protein tyrosine kinase inhibitors. J. Med. Chem. 32, 2344-2352.
13. Meydan, N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E., Lapidot, Z., Leeder, J. S., Freedman, M., Cohen, A., Gazit, A., Levitzki, A., and Roifman, C. M. (1996). Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379, 645-648.
14. Ito, T. and May, W. S. (1996). Drug development train gathering steam. Nat. Med. 2, 403.
15. Thompson, J. E., Cubbon, R. M., Cummings, R. T., Wicker, L. S., Frankshun, R., Cunningham, B. R., Cameron, P. M., Meinke, P. T., Liverton, N., Weng, Y., and DeMartino, J. A. (2002). Photochemical preparation of a pyridone containing tetracycle: a Jak protein kinase inhibitor. Bioorg. Med. Chem. Lett. 12, 1219-1223.
16. Posner, I. and Levitzki, A. (1994). Kinetics of phosphorylation of the SH2-containing domain of phospholipase C gamma 1 by the epidermal growth factor receptor. FEBS Lett. 353, 155-161.
17. Posner, I., Engel, M., Gazit, A., and Levitzki, A. (1994). Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program. Mol. Pharmacol. 45, 673-683.
18. Kovalenko, M., Ronnstrand, L., Heldin, C. H., Loubtchenkov, M., Gazit, A., Levitzki, A., and Bohmer, F. D. (1997). Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296. Biochemistry 36, 6260-6299.
19. Kovalenko, M., Gazit, A., Bohmer, A., Rorsman, C., Ronnstrand, L., Heldin, C. H., Waltenberger, J., Bohmer, F. D., and Levitzki, A. (1994). Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res. 54, 6106-6114.
20. Ward, W. H., Cook, P. N., Slater, A. M., Davies, D. H., Holdgate, G. A., and Green, L. R. (1994). Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem. Pharmacol. 48, 659-666.
21. Wakeling, A. E., Barker, A. J., Davies, D. H., Brown, D. S., Green, L. R., Cartlidge, S. A., and Woodburn, J. R. (1996). Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res. Treat. 38, 67-73.
22. Osherov, N. and Levitzki, A. (1994). Epidermal-growth-factor-dependent activation of the Src-family kinases. Eur. J. Biochem. 225, 1047-1053.
23. Levitzki, A. (1999). Protein tyrosine kinase inhibitors as novel therapeutic agents. Pharmacol. Ther. 82, 231-239.
24. Osherov, N., Gazit, A., Gilon, C., and Levitzki, A. (1993). Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J. Biol. Chem. 268, 11134-11142.
25. Woodburn, J. R., Barker, A. J., Gibson, K. H., Ashton, S. E., Wakeling, A. E., Curry, B. J., Scerlett, L., and Henthorn, L. R. (1997). Abstract 4251. Proc. 88th Annual Meeting AACR 38.
26. Gazit, A., App, H., McMahon, G., Chen, J., Levitzki, A., and Bohmer, F. D. (1996). Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor tyrosine kinase, structure-activity relationships in quinoxalines, quinolines, and indole tyrphostins. J. Med. Chem. 39, 2170-2177.
27. Levitzki, A., Gazit, A., Banai, S., Golomb, G., and Gertz, D. (2002). PDGF Receptor Kinase Inhibitory Compounds: Their Preparation, Purification and Pharmaceutical Compositions Including Same, U.S. Patent No. 6,358,954 .
28. Schindler, T., Sicheri, F., Pico, A., Gazit, A., Levitzki, A., and Kuriyan, J. (1999). Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor. Mol. Cell 3, 639-648.
29. Zhu, X., Kim, J. L., Newcomb, J. R., Rose, P. E., Stover, D. R., Toledo, L. M., Zhao, H., and Morgenstern, K. A. (1999). Protein, structure structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. Structure Fold Des. 7, 651-661.
30. Nagane, M., Levitzki, A., Gazit, A., Cavenee, W. K., and Huang, H. J. (1998). Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc. Natl. Acad. Sci. USA 95, 5724-5729.
31. Nagane, M., Narita, Y., Mishima, K., Levitzki, A., Burgess, A. W., Cavenee, W. K., and Huang, H. J. (2001). Human glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor. J. Neurosurg. 95, 472-479.
32. Norman, P. (2001). OSI-774 OSI Pharmaceuticals. Curr. Opin. Invest. Drugs 2, 298-304.
33. Keith, B. R., Allen, P. P., Aliigood, K. J., Crosby, R. M., Lackey, K., Gilmer, T. M., and Mullin, R. J. (2001). Abstract 4308. Proc. 92nd Annual Meeting AACR 42, 803.
34. Smaill, J. B., Rewcastle, G. W., Loo, J. A., Greis, K. D., Chan, O. H., Reyner, E. L., Lipka, E., Showalter, H. D., Vincent, P. W., Elliott, W. L., and Denny, W. A. (2000). Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino) quinazoline- and 4-(phenylamino)pyrido. J. Med. Chem. 43, 1380-1397.
35. Anafi, M., Gazit, A., Zehavi, A., Ben-Neriah, Y., and Levitzki, A. (1993). Tyrphostin-induced inhibition of p210Bcr-Abl tyrosine kinase activity induces K562 to differentiate. Blood 82, 3524-3529.
36. Anafi, M., Gazit, A., Gilon, C., Ben-Neriah, Y., and Levitzki, A. (1992). Selective interactions of transforming and normal Abl proteins with ATP, tyrosine-copolymer substrates, and tyrphostins. J. Biol. Chem. 267, 4518-4523.
37. Kaur, G., Gazit, A., Levitzki, A., Stowe, E., Cooney, D. A., and Sausville, E. A. (1994). Tyrphostin induced growth inhibition: correlation with effect on p210Bcr-Abl autokinase activity in K562 chronic myelogenous leukemia. Anticancer Drugs 5, 213-222.
38. Carlo-Stella, C., Regazzi, E., Sammarelli, G., Colla, S., Garau, D., Gazit, A., Savoldo, B., Cilloni, D., Tabilio, A., Levitzki, A., and Rizzoli, V. (1999). Effects of the tyrosine kinase inhibitor AG957 and an anti-Fas receptor antibody on CD34(+) chronic myelogenous leukemia progenitor cells. Blood 93, 3973-3982.
39. Druker, B. J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G. M., Fanning, S., Zimmermann, J., and Lydon, N. B. (1996). Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561-566.
40. Druker, B. J. and Lydon, N. B. (2000). Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J. Clin. Invest. 105, 3-7.
41. Druker, B. J. (2002). Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31-36.
42. Heinrich, M. C., Griffith, D. J., Druker, B. J., Wait, C. L., Ott, K. A., and Zigler, A. J. (2000). Inhibition of c-Kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925-932.
43. Novogrodsky, A., Vanichkin, A., Patya, M., Gazit, A., Osherov, N., and Levitzki, A. (1994). Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors. Science 264, 1319-1322.
44. Vanichkin, A., Patya, M., Gazit, A., Levitzki, A., and Novogrodsky, A. (1996). Late administration of a lipophilic tyrosine kinase inhibitor prevents lipopolysaccharide and Escherichia coli-induced lethal toxicity. J. Infect. Dis. 173, 927-933.
45. Sevransky, J. E., Shaked, G., Novogrodsky, A., Levitzki, A., Gazit, A., Hoffman, A., Elin, R. J., Quezado, Z. M., Freeman, B. D., Eichacker, P. Q., Danner, R. L., Banks, S. M., Bacher, J., Thomas, 3rd, M. L., and Natanson, C. (1997). Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. J. Clin. Invest. 99, 1966-1973.
46. Lopez-Talavera, J. C., Levitzki, A., Martinez, M., Gazit, A., Esteban, R., and Guardia, J. (1997). Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites. J. Clin. Invest. 100, 664-670.
47. Blum, G., Gazit, A., and Levitzk, A. (2000). Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry 39, 15705-15712.
48. Blum, G., Gazit, A., and Levitzki, A. (2002). Catechol bioisosteres substrate competitive inhibitors of IGF-1R (submitted).
49. Karni, R. and Levitzki, A. (2000). pp60(cSrc) is a caspase-3 substrate and is essential for the transformed phenotype of A431 cells. Mol. Cell. Biol. Res. Commun. 3, 98-104.
50. Hanke, J. H., Gardner, J. P., Dow, R. L., Changelian, P. S., Brissette, W. H., Weringer, E. J., Pollok, B. A., and Connelly, P. A. (1996). Discovery of a novel, potent, and Src-family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 271, 695-701.
51. Kami, R., Jove, R., and Levitzki, A. (1999). Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene 18, 4654-4662.
52. Waltenberger, J., Uecker, A., Kroll, J., Frank, H., Mayr, U., Bjorge, J. D., Fujita, D., Gazit, A., Hombach, V., Levitzki, A., and Bohmer, F. D. (1999). A dual inhibitor of platelet-derived growth factor beta-receptor and Src kinase activity potently interferes with motogenic and mito-genic responses to PDGF in vascular smooth muscle cells. A novel candidate for prevention of vascular remodeling. Circ. Res. 85, 12-22.
53. Laird, A. D., Vajkoczy, P., Shawver, L. K., Thurnher, A., Liang, C., Mohammadi, M., Schlessinger, J., Ullrich, A., Hubbard, S., Blake, R. A., Fong, T. A., Strawn, L. M., Sun, L., Tang, C., Hawtin, R., Tang, F., Shenoy, N., Hirth, K. P., McMahon, G., and Cherrington, G. (2000). SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152-4160.
54. Benhar, M., Dalyot, I., Engelberg, D., and Levitzki, A. (2001). Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol. Cell. Biol. 21, 6913-6926.
55. Tsai, C. M., Levitzki, A., Wu, L. H., Chang, K. T., Cheng, C. C., Gazit, A., and Perng, R. P. (1996). Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing non-small cell lung cancer cells. Cancer Res. 56, 1068-1074.
56. Sirotnak, F. M., Zakowski, M. F., Miller, V. A., Scher, H. I., and Kris, M. G. (2000). Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin. Cancer Res. 6, 4885-4892.
57. Catlett-Falcone, R., Landowski, T. H., Oshiro, M. M., Turkson, J., Levitzki, A., Savino, R., Ciliberto, G., Moscinski, L., Fernandez-Luna, J. L., Nunez, G., Dalton, W. S., and Jove, R. (1999). Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105-115.
58. Dvir, A., Milner, Y., Chomsky, O., Gilon, C., Gazit, A., and Levitzki, A. (1991). The inhibition of EGF-dependent proliferation of keratinocytes by tyrphostin tyrosine kinase blockers. J. Cell Biol. 113, 857-865.
59. Ben-Bassat, H., Vardi, D. V., Gazit, A., Klaus, S. N., Chaouat, M., Hartzstark, Z., and Levitzki, A. (1995). Tyrphostins suppress the growth of psoriatic keratinocytes. Exp. Dermatol. 4, 82-88.
60. Ben-Bassat, H. and Levitzki, A. (2000). Inhibitors of tyrosine kinases in the treatment of psoriasis. Isr. Med. Assoc. J. 2(suppl.), 69-73.
61. Powell, T. J., Ben-Bassat, H., Klein, B. Y., Chen, H., Shenoy, N., McCollough, J., Narog, B., Gazit, A., Harzstark, Z., Chaouat, M., Levitzki, R., Tang, C., McMahon, J., Shawver, L., and Levitzki, A. (1999). Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors. Br. J. Dermatol. 141, 802-810.
62. Ben-Bassat, H., Rosenbaum-Mitrani, S., Hartzstark, Z., Shlomai, Z., Kleinberger-Doron, N., Gazit, A., Plowman, G., Levitzki, R., Tsvieli, R., and Levitzki, A. (1997). Inhibitors of epidermal growth factor receptor kinase and of cyclin-dependent kinase 2 activation induce growth arrest, differentiation, and apoptosis of human papilloma virus 16-immortalized human keratinocytes. Cancer Res. 57, 3741-3750.
63. Ben-Bassat, H., Rosenbaum-Mitrani, S., Hartzstark, Z., Levitzki, R., Chaouat, M., Shlomai, Z., Klein, B. Y., Kleinberger-Doron, N., Gazit, A., Tsvieli, R., and Levitzki, A. (1999). Tyrphostins that suppress the growth of human papilloma virus 16-immortalized human ker-atinocytes. J. Pharmacol. Exp. Ther. 290, 1442-1457.
64. Banai, S., Wolf, Y., Golom, G., Pearle, A., Waltenberger, J., Fishbein, I., Schneider, A., Gazit, A., Perez, L., Huber, R., Lazarovichi, G., Rabinovich, L., Levitzki, A., and Gertz, S. D. (1998). PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine. Circulation 97, 1960-1969.
65. Lamartiniere, C. A., Cotroneo, M. S., Fritz, W. A., Wang, J., Mentor-Marcel, R., and Elgavish, A. (2002). Genistein chemopreven-tion, timing and mechanisms of action inmurine mammary and prostate. J. Nutr. 132, 5528-5588.
66. Kobayashi, T., Nakata, T., and Kuzumaki, T. (2002). Effect of flavonoids on cell cycle progression in prostate cancer cells. Cancer Lett. 176, 17-23.
67. Mentor-Marcel, R., Lamartiniere, C. A., Eltoum, I. E., Greenberg, N. M., and Elgavish, A. (2001). Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP). Cancer Res. 61, 6777-6782.
68. Bergan, R. C., Waggle, D. H., Carter, S. K., Horak, I., Slichenmyer, W., and Meyers, M. (2001). Tyrosine kinase inhibitors and signal trans-duction modulators: rationale and current status as chemopreventive agents for prostate cancer. Urology 57, 77-80.
69. Fritz, W. A., Wang, J., Eltoum, I. E., and Lamartiniere, C. A. (2002). Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate. Mol. Cell. Endocrinol. 186, 89-99.
70. Bonasera, T. A., Ortu, G., Rozen, Y., Krais, R., Freedman, N. M., Chisin, R., Gazit, A., Levitzki, A., and Mishani, E. (2001). Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase. Nucl. Med. Biol. 28, 359-374.
71. Ortu, G., Ben David, I., Rozen, Y., Freedman, N. M., Chisin, R., Levitzki, A., and Mishani, E. (2002). In vitro and in vivo investigation of an irreversible labeled EGFR inhibitor (ML03) and its potential as PET biomarker in cancer and feasibility as an anticancer drug. Int. J. Cancer (in press).
72. Reuveni, H., Livnah, N., Geiger, T., Klen, S., Ohne, O., Cohen, I., Benhar, M., Gellerman, G., and Levitzki, A. (2002). Towards a PKB inhibitor: modification of a selective PKA inhibitor by rational design. Biochemistry (in press).
73. Davies, H., Bignell, G. R., Cox, C. et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417, 949-954.
74. Lyons, J. F., Wilhelm, S., Hibner, B., and Bollag, G. (2001). Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer 3, 219-225.
75. Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., and Saltiel, A. R. (1999). Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. 5, 810-816.
76. Sausville, E. A., Johnson, J., Alley, M., Zaharevitz, D., and Senderowicz, A. M. (2000). Inhibition of CDKs as a therapeutic modality. Ann. N.Y. Acad. Sci. 221-222.
77. Kaubisch, A. and Schwartz, G. K. (2000). Cyclin-dependent kinase and protein kinase C inhibitors: a novel class of antineoplastic agents in clinical development. Cancer J. 6, 192-212.
78. Mani, S., Wang, C., Wu, K., Francis, R., and Pestell, R. (2000). Cyclin-dependent kinase inhibitors, novel anticancer agents. Expert Opin. Invest. Drugs 9, 1849-1870.
79. Murthi, K. K., Dubay, M., McClure, C., Brizuela, L., Boisclair, M. D., Worland, P. J., Mansuri, M. M., and Pal, K. (2000). Structure-activity relationship studies of flavopiridol analogues. Bioorg. Med. Chem. Lett. 10, 1037-1041.
80. Roy, K. K. and Sausville, E. A. (2001). Early development of cyclin dependent kinase modulators. Curr. Pharm. Des. 7, 1669-1687.
81. Sausville, E. A. (2002). Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol. Med. 8, S32-S37.
82. Kelland, L. R. (2000). Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. Expert Opin. Invest. Drugs 9, 2903-2911.
83. Senderowicz, A. M. (1999). Flavopiridol, the first cyclin-dependent kinase inhibitor in human clinical trials. Invest. New Drugs 17, 313-320.
84. da Rocha, A. B., Mans, D. R., Regner, A., and Schwartsmann, G. (2002). Targeting protein kinase C: new therapeutic opportunities against high-grade malignant gliomas? Oncologist 7, 17-33.
85. Goekjian, P. G. and Jirousek, M. R. (2001). Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Invest. Drugs 10, 2117-2140.
86. Teicher, B. A., Alvarez, E., Menon, K., Esterman, M. A., Considine, E., Shih, C., and Faul, M. M. (2002). Antiangiogenic effects of a protein kinase Cbeta-selective small molecule. Cancer Chemother. Pharmacol. 49, 69-77.
87. Ishii, H., Jirousek, M. R., Koya, D., Takagi, C., Xia, P., Clermont, A., Bursell, S. E., Kern, T. S., Ballas, L. M., Heath, W. F., Stramm, L. E., Feener, E. P., and King, G. L. (1996). Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272, 728-731.
88. Guba, M., von Breitenbuch, P., Steinbauer, M., Koehl, G., Flegel, S., Hornung, M., Bruns, C. J., Zuelke, C., Farkas, S., Anthuber, M., Jauch, K. W., and Geissler, E. K. (2002). Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med. 8, 128-135.
89. Morice, M. C., Serruys, P. W., Sousa, J. E., Fajadet, J., Ban Hayashi, E., Perin, M., Colombo, A., Schuler, G., Barragan, P., Guagliumi, G., Molnar, F., and Falotico, R. (2002). A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascular-ization. N. Engl. J. Med. 346, 1773-1780.
Was this article helpful?
How To Maintain The Stop Smoking Pledge From Your New Year’s Resolution. Get All The Support And Guidance You Need To Be A Success At Quitting Smoking. This Book Is One Of The Most Valuable Resources In The World When It Comes To How To Maintain The Stop Smoking Pledge From Your New Year’s Resolution.