Teodoro_subbed.qxp 27/11/08 05:01 Page 18
Current Issues
mechanisms of these signals seem to be more complex than their than patients receiving chemotherapy alone.
30
Endostar has now been
proangiogenic counterparts. For example, Tsp-1 has been reported to approved for the treatment of lung cancer in China and trials are in
interact with several different receptors, although much of the angiostatic progress for the treatment of other cancer types.
activity is thought to be mediated through the CD36 receptor. The use of
Tsp-1 as a therapeutic is also complicated by the fact that it is a very large We have observed the p53 tumor suppressor to stimulate the release of
protein that would be difficult to produce in sufficient quantities for at least two different CDAFs, endostatin and tumstatin.
25
It is likely that
treatment. This is not the case for the CDAFs, which are relatively small using cocktails of CDAFs may prove more effective. CDAFs function by
16–20kDa peptides and can be adapted almost directly as drugs. binding to integrin molecules on endothelial cells, and each CDAF has
slightly different properties.
31
Since p53 can stimulate production of at
There is evidence that increasing production of CDAFs can have a least two different CDAFs, using such mixtures may be a more effective
significant effect on tumor growth. Studies in mice have shown that method of shutting down angiogenesis. Another strategy used by p53
increasing levels of endostatin by only 1.6-fold can result in lower tumor that may prove clinically relevant is to utilize therapies that target
growth.
28
In this same study it was also shown that mice lacking the proangiogenic signals such as VEGF in combination with CDAFs. Drugs
expression of the CDAFs endostatin or tumstatin result in two- to that target VEGF such as bevacizumab have been approved for treatment
three-fold faster tumor growth. Unfortunately, when phase II clinical of lung and colorectal cancer and are able to extend the life of patients
trials for endostatin were carried out for the treatment of advanced by four to six months. Unfortunately, tumors eventually develop
neuroendocrine tumors, no significant tumor regression was observed.
29
resistance to these medications and evolve other routes by which to
The lack of response in this study may have been due to the type and late promote angiogenesis. Preventing tumor vascularization may be
stage of the cancers under study, as well as the protocol of using analogous to fighting infectious diseases such as HIV. The control of
endostatin as a monotherapy. Since this initial report, no further trials angiogenesis in cancer may be achieved only through the application of
using CDAFs have been carried out at any sites in North America or well-designed cocktails of drugs targeting several aspects of
Europe. However, several clinical trials are being carried out in China angiogenesis biology. Tumor-suppressor proteins such as p53 are able to
using a modified version of endostatin called Endostar. Results of trials hold angiogenesis in check for extended periods of time, and studying
using chemotherapy in combination with Endostar for treatment of lung such pathways may provide insights toward how tumor angiogenesis can
cancer have been reported to show significantly greater tumor regression be controlled in the clinic. ■
1. Bergers G, Benjamin LE, Tumorigenesis and the angiogenic carcinoma of the thyroid. A ‘normal’ finding in Finland. A apoptotic network, Cancer Res, 2005;65(12):5096–104.
switch, Nat Rev Cancer, 2003;3(6):401–10. systematic autopsy study, Cancer, 1985;56(3):531–8. 27. Wei CL, Wu Q, Vega VB, et al., A global map of p53
2. Hollstein M, Sidransky D, Vogelstein B, et al., p53 mutations in 14. Folkman J, Long DM Jr, Becker FF, Growth and metastasis of transcription-factor binding sites in the human genome, Cell,
human cancers, Science, 1991;253(5015):49–53. tumor in organ culture, Cancer, 1963;16:453–67. 2006;124(1):207–19.
3. Greenblatt MS, Bennett WP, Hollstein M, et al., Mutations in the 15. Vousden KH, Lu X, Live or let die: the cell’s response to p53, 28. Sund M, Hamano Y, Sugimoto H, et al., Function of endogenous
p53 tumor suppressor gene: clues to cancer etiology and Nat Rev Cancer, 2002;2(8):594–604. inhibitors of angiogenesis as endothelium-specific tumor
molecular pathogenesis, Cancer Res, 1994;54(18):4855–78. 16. Pugh CW, Ratcliffe PJ, Regulation of angiogenesis by hypoxia: suppressors, Proc Natl Acad Sci U S A, 2005;102(8):2934–9.
4. Yu EY, Yu E, Meyer GE, et al., The relation of p53 protein role of the HIF system, Nat Med, 2003;9(6):677–84. 29. Kulke MH, Bergsland EK, Ryan DP, et al., Phase II study of
nuclear accumulation and angiogenesis in human prostatic 17. Ravi R, Mookerjee B, Bhujwalla ZM, et al., Regulation of tumor recombinant human endostatin in patients with advanced
carcinoma, Prostate Cancer Prostatic Dis, 1997;1(1):39–44. angiogenesis by p53-induced degradation of hypoxia-inducible neuroendocrine tumors, J Clin Oncol, 2006;24(22):3555–61.
5. Takahashi Y, Bucana CD, Cleary KR, et al., p53, vessel count, factor 1alpha, Genes Dev, 2000;14(1):34–44. 30. Sun Y, Wang J, Liu Y, et al., Results of Phase III trial of
and vascular endothelial growth factor expression in human 18. Ho J, Benchimol S, Transcriptional repression mediated by the EndostarTM (rh-endostatin, YH-16) in advanced non-small lung
colon cancer, Int J Cancer, 1998;79(1):34–8. p53 tumour suppressor, Cell Death Differ, 2003;10(4):404–8. cancer (NSCLC) patients 2005 ASCO Annual Meeting. Orlando,
6. Kang SM, Maeda K, Onoda N, et al., Combined analysis of p53 19. Pal S, Datta K, Mukhopadhyay D, Central role of p53 on J Clin Oncol, 2005;23:16S.
and vascular endothelial growth factor expression in colorectal regulation of vascular permeability factor/vascular endothelial 31. Assadian S, Teodoro JG, Regulation of collagen-derived
carcinoma for determination of tumor vascularity and liver growth factor (VPF/VEGF) expression in mammary carcinoma, antiangiogenic factors by p53, Exp Opinion Biol Ther, 2008;8(7):
metastasis, Int J Cancer, 1997;74(5):502–7. Cancer Res, 2001;61(18):6952–7. 941–50.
7. Gasparini G, Weidner N, Bevilacqua P, et al., Tumor microvessel 20. Ueba T, Nosaka T, Takahashi JA, et al., Transcriptional regulation 32. O’Reilly MS, Boehm T, Shing Y, et al., Endostatin: an
density, p53 expression, tumor size, and peritumoral lymphatic of basic fibroblast growth factor gene by p53 in human endogenous inhibitor of angiogenesis and tumor growth, Cell,
vessel invasion are relevant prognostic markers in node- glioblastoma and hepatocellular carcinoma cells, Proc Natl Acad 1997;88(2):277–85.
negative breast carcinoma, J Clin Oncol, 1994;12(3):454–66. Sci U S A, 1994;91(19):9009–13. 33. Ramchandran R, Dhanabal M, Volk R, et al., Antiangiogenic
8. Gasparini G, Weidner N, Maluta S, et al., Intratumoral 21. Subbaramaiah K, Altorki N, Chung WJ, et al., Inhibition of activity of restin, NC10 domain of human collagen XV:
microvessel density and p53 protein: correlation with metastasis cyclooxygenase-2 gene expression by p53, J Biol Chem, comparison to endostatin, Biochem Biophys Res Commun,
in head-and-neck squamous-cell carcinoma, Int J Cancer, 1999;274(16):10911–15. 1999;255(3):735–9.
1993;55(5):739–44. 22. Iniguez MA, Rodriguez A, Volpert OV, et al., Cyclooxygenase-2: 34. Colorado PC, Torre A, Kamphaus G, et al., Antiangiogenic cues
9. Giuriato S, Ryeom S, Fan AC, et al., Sustained regression of a therapeutic target in angiogenesis, Trends Mol Med, from vascular basement membrane collagen, Cancer Res,
tumors upon MYC inactivation requires p53 or 2003;9(2):73–8. 2000;60(9):2520–26.
thrombospondin-1 to reverse the angiogenic switch, Proc Natl 23. Dameron KM, Volpert OV, Tainsky MA, et al., The p53 tumor 35. Kamphaus GD, Colorado PC, Panka DJ, et al., Canstatin, a novel
Acad Sci U S A, 2006;103(44):16266–71. suppressor gene inhibits angiogenesis by stimulating the matrix-derived inhibitor of angiogenesis and tumor growth, J
10. Holmgren L, Jackson G, Arbiser J, p53 induces angiogenesis- production of thrombospondin, Cold Spring Harb Symp Quant Biol Chem, 2000;275(2):1209–15.
restricted dormancy in a mouse fibrosarcoma, Oncogene, Biol, 1994;59:483–9. 36. Maeshima Y, Colorado PC, Torre A, et al., Distinct antitumor
1998;17(7):819–24. 24. Ren B, Yee KO, Lawler J, et al., Regulation of tumor properties of a type IV collagen domain derived from basement
11. Gautam A, Densmore CL, Melton S, et al., Aerosol delivery of angiogenesis by thrombospondin-1, Biochim Biophys Acta, membrane, J Biol Chem, 2000;275(28):21340–48.
PEI-p53 complexes inhibits B16-F10 lung metastases through 2006;1765(2):178–88. 37. Petitclerc E, Boutaud A, Prestayko A, et al., New functions for
regulation of angiogenesis, Cancer Gene Ther, 2002;9(1):28–36. 25. Teodoro JG, Parker AE, Zhu X, et al., p53-mediated inhibition of non-collagenous domains of human collagen type IV. Novel
12. Black WC, Welch HG, Advances in diagnostic imaging and angiogenesis through up-regulation of a collagen prolyl integrin ligands inhibiting angiogenesis and tumor growth in
overestimations of disease prevalence and the benefits of hydroxylase, Science, 2006;313(5789):968–71. vivo, J Biol Chem, 2000;275(11):8051–61.
therapy, N Engl J Med, 1993;328(17):1237–43. 26. Miled C, Pontoglio M, Garbay S, et al., A genomic map of p53
13. Harach HR, Franssila KO, Wasenius VM, Occult papillary binding sites identifies novel p53 targets involved in an
18 US ONCOLOGY