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Published in:

01-12-2007 | Topic Paper

p53 and retinoblastoma pathways in bladder cancer

Authors: Anirban P. Mitra, Marc Birkhahn, Richard J. Cote

Published in: World Journal of Urology | Issue 6/2007

Abstract

A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma genes and pathways. Examination of the alterations in the molecules in these pathways that regulate the cell cycle and their effects on the prognosis of bladder cancer are areas of active research. While defects in the p53-Mdm2-p14 axis have been implicated in urothelial cancer, perturbations in the cyclin-dependent kinases and their inhibitors have also been extensively studied in this context. Genetic alterations of the retinoblastoma gene and aberrant post-translational modifications of its protein have also been incriminated in invasive bladder cancer. This article reviews the individual prognostic roles of alterations in these molecules in the context of bladder cancer. Additionally, we review findings from recent studies that are attempting to analyze these markers in combination in an effort to construct molecular panels that can serve as more robust outcome predictors. More importantly, alterations in these molecules are now becoming enticing targets for novel therapeutics. We also review some of these agents that can restore the tumor cells’ altered homeostatic mechanisms, thereby having potential in transitional cell carcinoma therapy. Future management of bladder cancer will employ validated marker panels for outcome prediction, and novel genetic and pharmacologic agents that will be able to target molecular alterations in individual tumors based on their respective profiles.

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66PubMed

Mitra AP, Datar RH, Cote RJ (2006) Molecular pathways in invasive bladder cancer: New insights into mechanisms, progression, and target identification. J Clin Oncol 24:5552–5564. doi: 10.1200/JCO.2006.08.2073 PubMedCrossRef

Zhang ZT, Pak J, Huang HY, Shapiro E, Sun TT, Pellicer A, Wu XR (2001) Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20:1973–1980PubMedCrossRef

Bakkar AA, Wallerand H, Radvanyi F, Lahaye JB, Pissard S, Lecerf L, Kouyoumdjian JC, Abbou CC, Pairon JC, Jaurand MC, Thiery JP, Chopin DK, de Medina SG (2003) FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res 63:8108–8112PubMed

Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823PubMedCrossRef

Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedCrossRef

Linzer DI, Levine AJ (1979) Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52. doi: 10.1016/0092-8674(79)90293-9 PubMedCrossRef

DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci USA 76:2420–2424PubMedCrossRef

Finlay CA, Hinds PW, Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093. doi: 10.1016/0092-8674(89)90045-7 PubMedCrossRef

10.

Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221. doi:10.1126/science.2649981 PubMedCrossRef

11.

Mitra AP, Lin H, Datar RH, Cote RJ (2006) Molecular biology of bladder cancer: prognostic and clinical implications. Clin Genitourin Cancer 5:67–77PubMedCrossRef

12.

Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70:923–935. doi: 10.1016/0092-8674(92)90243-6 PubMedCrossRef

13.

el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825. doi: 10.1016/0092-8674(93)90500-P PubMedCrossRef

14.

Olumi AF, Tsai YC, Nichols PW, Skinner DG, Cain DR, Bender LI, Jones PA (1990) Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinomas of the bladder. Cancer Res 50:7081–7083PubMed

15.

Dalbagni G, Presti JC Jr, Reuter VE, Zhang ZF, Sarkis AS, Fair WR, Cordon-Cardo C (1993) Molecular genetic alterations of chromosome 17 and p53 nuclear overexpression in human bladder cancer. Diagn Mol Pathol 2:4–13PubMed

16.

Cote RJ, Chatterjee SJ (1999) Molecular determinants of outcome in bladder cancer. Cancer J Sci Am 5:2–15PubMed

17.

Fujimoto K, Yamada Y, Okajima E, Kakizoe T, Sasaki H, Sugimura T, Terada M (1992) Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 52:1393–1398PubMed

18.

Esrig D, Spruck CH 3rd, Nichols PW, Chaiwun B, Steven K, Groshen S, Chen SC, Skinner DG, Jones PA, Cote RJ (1993) p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 143:1389–1397PubMed

19.

Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, Esrig D, Miyao N, Tsai YC, Lerner SP, Schmutte C, Yang AS, Cote R, Dubeau L, Nichols PW, Hermann GG, Steven K, Horn T, Skinner DG, Jones PA (1994) Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54:784–788PubMed

20.

Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG (2001) Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666–675PubMed

21.

Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC, Nichols PW, Skinner DG, Jones PA, Cote RJ (1994) Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331:1259–1264PubMedCrossRef

22.

Stein JP, Ginsberg DA, Grossfeld GD, Chatterjee SJ, Esrig D, Dickinson MG, Groshen S, Taylor CR, Jones PA, Skinner DG, Cote RJ (1998) Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90:1072–1079PubMedCrossRef

23.

Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7:1126–1132PubMedCrossRef

24.

Simon R, Struckmann K, Schraml P, Wagner U, Forster T, Moch H, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T, Sauter G (2002) Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene 21:2476–2483PubMedCrossRef

25.

Orlow I, LaRue H, Osman I, Lacombe L, Moore L, Rabbani F, Meyer F, Fradet Y, Cordon-Cardo C (1999) Deletions of the INK4A gene in superficial bladder tumors. Association with recurrence. Am J Pathol 155:105–113PubMed

26.

Berggren P, Kumar R, Sakano S, Hemminki L, Wada T, Steineck G, Adolfsson J, Larsson P, Norming U, Wijkstrom H, Hemminki K (2003) Detecting homozygous deletions in the CDKN2A(p16 ^INK4a)/ARF(p14 ^ARF) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res 9:235–242PubMed

27.

Knudson AG Jr (1978) Retinoblastoma: A prototypic hereditary neoplasm. Semin Oncol 5:57–60PubMed

28.

Horowitz JM, Yandell DW, Park SH, Canning S, Whyte P, Buchkovich K, Harlow E, Weinberg RA, Dryja TP (1989) Point mutational inactivation of the retinoblastoma antioncogene. Science 243:937–940. doi:10.1126/science.2521957 PubMedCrossRef

29.

Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW, Kaye FJ, Minna JD, Dryja TP, Weinberg RA (1990) Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 87:2775–2779. doi:10.1073/pnas.87.7.2775 PubMedCrossRef

30.

Takahashi R, Hashimoto T, Xu HJ, Hu SX, Matsui T, Miki T, Bigo-Marshall H, Aaronson SA, Benedict WF (1991) The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells. Proc Natl Acad Sci USA 88:5257–5261. doi:10.1073/pnas.88.12.5257 PubMedCrossRef

31.

Cairns P, Proctor AJ, Knowles MA (1991) Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. Oncogene 6:2305–2309PubMed

32.

Cordon-Cardo C, Wartinger D, Petrylak D, Dalbagni G, Fair WR, Fuks Z, Reuter VE (1992) Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst 84:1251–1256PubMedCrossRef

33.

Logothetis CJ, Xu HJ, Ro JY, Hu SX, Sahin A, Ordonez N, Benedict WF (1992) Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 84:1256–1261PubMedCrossRef

34.

Miyamoto H, Shuin T, Torigoe S, Iwasaki Y, Kubota Y (1995) Retinoblastoma gene mutations in primary human bladder cancer. Br J Cancer 71:831–835PubMed

35.

Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR (1991) The E2F transcription factor is a cellular target for the RB protein. Cell 65:1053–1061. doi:10.1016/0092-8674(91)90557-F PubMedCrossRef

36.

Schafer KA (1998) The cell cycle: A review. Vet Pathol 35:461–478PubMedCrossRef

37.

DeGregori J, Kowalik T, Nevins JR (1995) Cellular targets for activation by the E2F1 transcription factor include DNA synthesis-and G₁/S-regulatory genes. Mol Cell Biol 15:4215–4224PubMed

38.

Grossman HB, Liebert M, Antelo M, Dinney CP, Hu SX, Palmer JL, Benedict WF (1998) p53 and RB expression predict progression in T₁ bladder cancer. Clin Cancer Res 4:829–834PubMed

39.

Cote RJ, Dunn MD, Chatterjee SJ, Stein JP, Shi SR, Tran QC, Hu SX, Xu HJ, Groshen S, Taylor CR, Skinner DG, Benedict WF (1998) Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res 58:1090–1094PubMed

40.

Chatterjee SJ, George B, Goebell PJ, Alavi-Tafreshi M, Shi SR, Fung YK, Jones PA, Cordon-Cardo C, Datar RH, Cote RJ (2004) Hyperphosphorylation of pRb: A mechanism for RB tumour suppressor pathway inactivation in bladder cancer. J Pathol 203:762–770. doi:10.1002/path.1567 PubMedCrossRef

41.

Aaboe M, Marcussen N, Jensen KM, Thykjaer T, Dyrskjot L, Orntoft TF (2005) Gene expression profiling of noninvasive primary urothelial tumours using microarrays. Br J Cancer 93:1182–1190PubMedCrossRef

42.

Reznikoff CA, Sarkar S, Julicher KP, Burger MS, Puthenveettil JA, Jarrard DF, Newton MA (2000) Genetic alterations and biological pathways in human bladder cancer pathogenesis. Urol Oncol 5:191–203. doi:10.1016/S1078-1439(00)00079-X PubMedCrossRef

43.

Takagi Y, Takashi M, Koshikawa T, Sakata T, Ohshima S (2000) Immunohistochemical demonstration of cyclin D1 in bladder cancers as an inverse indicator of invasiveness but not an independent prognostic factor. Int J Urol 7:366–372. doi:10.1046/j.1442-2042.2000.00212.x PubMedCrossRef

44.

Shariat SF, Ashfaq R, Sagalowsky AI, Lotan Y (2006) Correlation of cyclin D1 and E1 expression with bladder cancer presence, invasion, progression, and metastasis. Hum Pathol 37:1568–1576. doi:10.1016/j.humpath.2006.05.017 PubMedCrossRef

45.

Tut VM, Braithwaite KL, Angus B, Neal DE, Lunec J, Mellon JK (2001) Cyclin D1 expression in transitional cell carcinoma of the bladder: Correlation with p53, waf1, pRb and Ki67. Br J Cancer 84:270–275. doi:10.1054/bjc.2000.1557 PubMedCrossRef

46.

Garcia-Espana A, Salazar E, Sun T-T, Wu X-R, Pellicer A (2005) Differential expression of cell cycle regulators in phenotypic variants of transgenically induced bladder tumors: Implications for tumor behavior. Cancer Res 65:1150–1157PubMedCrossRef

47.

Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J (1994) Cloning of p27^Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59–66. doi:10.1016/0092-8674(94)90572-X PubMedCrossRef

48.

Coats S, Flanagan WM, Nourse J, Roberts JM (1996) Requirement of p27^Kip1 for restriction point control of the fibroblast cell cycle. Science 272:877–880. doi: 10.1126/science.272.5263.877PubMedCrossRef

49.

Sun D, Ren H, Oertel M, Sellers RS, Zhu L (2007) Loss of p27^Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation. Carcinogenesis (in press)

50.

Osoegawa A, Yoshino I, Tanaka S, Sugio K, Kameyama T, Yamaguchi M, Maehara Y (2004) Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer. J Clin Oncol 22:4165–4173. doi:10.1200/JCO.2004.01.035 PubMedCrossRef

51.

Cote RJ, Shi Y, Groshen S, Feng AC, Cordon-Cardo C, Skinner D, Lieskovosky G (1998) Association of p27^Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst 90:916–920PubMedCrossRef

52.

Kamai T, Takagi K, Asami H, Ito Y, Oshima H, Yoshida KI (2001) Decreasing of p27^Kip1 and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer. Br J Cancer 84:1242–1251. doi:10.1054/bjc.2000.1736 PubMedCrossRef

53.

Sgambato A, Migaldi M, Faraglia B, Garagnani L, Romano G, De Gaetani C, Ferrari P, Capelli G, Trentini GP, Cittadini A (1999) Loss of P27^Kip1 expression correlates with tumor grade and with reduced disease-free survival in primary superficial bladder cancers. Cancer Res 59:3245–3250PubMed

54.

Franke KH, Miklosi M, Goebell P, Clasen S, Steinhoff C, Anastasiadis AG, Gerharz C, Schulz WA (2000) Cyclin-dependent kinase inhibitor P27^Kip1 is expressed preferentially in early stages of urothelial carcinoma. Urology 56:689–695. doi:10.1016/S0090-4295(00)00678-6 PubMedCrossRef

55.

Schrier BP, Vriesema JL, Witjes JA, Kiemeney LA, Schalken JA (2006) The predictive value of p53, p27^Kip1, and alpha-catenin for progression in superficial bladder carcinoma. Eur Urol 50:76–82. doi:10.1016/j.eururo.2005.12.041 PubMedCrossRef

56.

Halling KC, King W, Sokolova IA, Karnes RJ, Meyer RG, Powell EL, Sebo TJ, Cheville JC, Clayton AC, Krajnik KL, Ebert TA, Nelson RE, Burkhardt HM, Ramakumar S, Stewart CS, Pankratz VS, Lieber MM, Blute ML, Zincke H, Seelig SA, Jenkins RB, O’Kane DJ (2002) A comparison of BTA stat, hemoglobin dipstick, telomerase and Vysis UroVysion assays for the detection of urothelial carcinoma in urine. J Urol 167:2001–2006PubMedCrossRef

57.

Chatterjee SJ, Datar R, Youssefzadeh D, George B, Goebell PJ, Stein JP, Young L, Shi SR, Gee C, Groshen S, Skinner DG, Cote RJ (2004) Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol 22:1007–1013PubMedCrossRef

58.

Shariat SF, Tokunaga H, Zhou J, Kim J, Ayala GE, Benedict WF, Lerner SP (2004) p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol 22:1014–1024PubMedCrossRef

59.

Shariat SF, Zlotta AR, Ashfaq R, Sagalowsky AI, Lotan Y (2007) Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness. Mod Pathol 20:445–459. doi:10.1038/modpathol.3800757 PubMedCrossRef

60.

Lu ML, Wikman F, Orntoft TF, Charytonowicz E, Rabbani F, Zhang Z, Dalbagni G, Pohar KS, Yu G, Cordon-Cardo C (2002) Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods. Clin Cancer Res 8:171–179PubMed

61.

Hitchings AW, Kumar M, Jordan S, Nargund V, Martin J, Berney DM (2004) Prediction of progression in pTa and pT1 bladder carcinomas with p53, p16 and pRb. Br J Cancer 91:552–557. doi:10.1038/sj.bjc.6601954 PubMedCrossRef

62.

Mitra AP, Lin H, Cote RJ, Datar RH (2005) Biomarker profiling for cancer diagnosis, prognosis and therapeutic management. Natl Med J India 18:304–312PubMed

63.

Mitra AP, Datar RH, Cote RJ (2005) Molecular staging of bladder cancer. BJU Int 96:7–12. doi:10.1111/j.1464-410X.2005.05557.x PubMedCrossRef

64.

Mitra AP, Almal AA, George B, Fry DW, Lenehan PF, Pagliarulo V, Cote RJ, Datar RH, Worzel WP (2006) The use of genetic programming in the analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer. BMC Cancer 6:159. doi:10.1186/1471-2407-6-159 PubMedCrossRef

65.

Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG (1997) p53 and treatment of bladder cancer. Nature 385:123–125. doi:10.1038/385123b0 PubMedCrossRef

66.

Waldman T, Lengauer C, Kinzler KW, Vogelstein B (1996) Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381:713–716. doi:10.1038/381713a0 PubMedCrossRef

67.

Cote RJ, Datar RH (2003) Therapeutic approaches to bladder cancer: Identifying targets and mechanisms. Crit Rev Oncol Hematol 46:S67–S83. doi:10.1016/S1040-8428(03)00066-0 PubMedCrossRef

68.

Werthman PE, Drazan KE, Rosenthal JT, Khalili R, Shaked A (1996) Adenoviral-p53 gene transfer to orthotopic and peritoneal murine bladder cancer. J Urol 155:753–756. doi:10.1016/S0022-5347(01)66515-7 PubMedCrossRef

69.

Pagliaro LC (2000) Gene therapy for bladder cancer. World J Urol 18:148–151. doi:10.1007/s003450050188 PubMedCrossRef

70.

Kuball J, Wen SF, Leissner J, Atkins D, Meinhardt P, Quijano E, Engler H, Hutchins B, Maneval DC, Grace MJ, Fritz MA, Storkel S, Thuroff JW, Huber C, Schuler M (2002) Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol 20:957–965PubMedCrossRef

71.

Pagliaro LC, Keyhani A, Williams D, Woods D, Liu B, Perrotte P, Slaton JW, Merritt JA, Grossman HB, Dinney CP (2003) Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: A phase I study of p53 gene therapy. J Clin Oncol 21:2247–2253PubMedCrossRef

72.

Pagliaro LC, Keyhani A, Liu B, Perrotte P, Wilson D, Dinney CP (2003) Adenoviral p53 gene transfer in human bladder cancer cell lines: Cytotoxicity and synergy with cisplatin. Urol Oncol 21:456–462. doi:10.1016/S1078-1439(03)00032-2 PubMed

73.

Gomella LG, Mastrangelo MJ, McCue PA, Maguire HC JR, Mulholland SG, Lattime EC (2001) Phase I study of intravesical vaccinia virus as a vector for gene therapy of bladder cancer. J Urol 166:1291–1295. doi:10.1016/S0022-5347(05)65755-2 PubMedCrossRef

74.

Fodor I, Timiryasova T, Denes B, Yoshida J, Ruckle H, Lilly M (2005) Vaccinia virus mediated p53 gene therapy for bladder cancer in an orthotopic murine model. J Urol 173:604–609. doi:10.1097/01.ju.0000143196.37008.2c PubMedCrossRef

75.

Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8:282–288. doi:10.1038/nm0302-282 PubMedCrossRef

76.

Bykov VJ, Zache N, Stridh H, Westman J, Bergman J, Selivanova G, Wiman KG (2005) PRIMA-1^MET synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 24:3484–3491. doi:10.1038/sj.onc.1208419 PubMedCrossRef

77.

Xu HJ, Zhou Y, Seigne J, Perng GS, Mixon M, Zhang C, Li J, Benedict WF, Hu SX (1996) Enhanced tumor suppressor gene therapy via replication-deficient adenovirus vectors expressing an N-terminal truncated retinoblastoma protein. Cancer Res 56:2245–2249PubMed

78.

Zhang X, Multani AS, Zhou JH, Shay JW, McConkey D, Dong L, Kim CS, Rosser CJ, Pathak S, Benedict WF (2003) Adenoviral-mediated retinoblastoma 94 produces rapid telomere erosion, chromosomal crisis, and caspase-dependent apoptosis in bladder cancer and immortalized human urothelial cells but not in normal urothelial cells. Cancer Res 63:760–765PubMed

79.

Schnier JB, Nishi K, Goodrich DW, Bradbury EM (1996) G₁ arrest and down-regulation of cyclin E/cyclin-dependent kinase 2 by the protein kinase inhibitor staurosporine are dependent on the retinoblastoma protein in the bladder carcinoma cell line 5637. Proc Natl Acad Sci USA 93:5941–5946. doi:10.1073/pnas.93.12.5941 PubMedCrossRef

80.

Senderowicz AM (2003) Novel small molecule cyclin-dependent kinases modulators in human clinical trials. Cancer Biol Ther 2:S84–S95PubMed

81.

Senderowicz AM (2003) Small-molecule cyclin-dependent kinase modulators. Oncogene 22:6609–6620. doi:10.1038/sj.onc.120 PubMedCrossRef

Title: p53 and retinoblastoma pathways in bladder cancer
Authors: Anirban P. Mitra
Marc Birkhahn
Richard J. Cote
Publication date: 01-12-2007
Publisher: Springer-Verlag
Published in: World Journal of Urology / Issue 6/2007
Print ISSN: 0724-4983
Electronic ISSN: 1433-8726
DOI: https://doi.org/10.1007/s00345-007-0197-0

At a glance: The STEP trials

Springer Medicine

p53 and retinoblastoma pathways in bladder cancer

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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