Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

B.Chemotherapy

1.Epipodophyllotoxin-Induced Secondary Leukemia

The epipodophyllotoxins, etoposide and teniposide, are included in most of the protocols for retinoblastoma. By inhibiting the normal religation activity of the nuclear enzyme topoisomerase II, these drugs can induce secondary leukemia characterized by site-specific DNA rearrangements. Secondary leukemia often has a short latency period, appearing within 2 years of epipodophyllotoxin therapy. Both high cumulative doses [164–167] and intensive schedules of administration [168] may contribute to the clinical risk.

Smith et al. recently reported the cumulative 6-year risk of leukemia for patients treated on 12 prospectively tracked protocols with different epipodophyllotoxin schedules combined with other chemotherapy and radiation, suggesting that factors other than epipodophyllotoxin cumulative doses may determine the risk of secondary leukemia [169]. There are also no data addressing the possibility that a greater systemic exposure to etoposide in the presence of CSA [170,171] increases the risk of secondary leukemia. Recently, high cumulative carboplatin doses have also been implicated as a risk factor for induction of secondary leukemia in ovarian cancer patients [172].

2.The Leukemic Risk of Patients with Retinoblastoma

Fortunately, children with RB1 germline mutations do not have an increased predisposition for leukemia [173,174], despite their increased risk for other types of solid tumors [174]. M5 acute myelogenous leukemia developed after a latent period of only 2 months in a retinoblastoma patient treated with vincristine, doxorubicin, and cyclophosphamide [175]. There are five unpublished cases of myeloid leukemia in retinoblastoma patients who reportedly had received both etoposide and carboplatin. It is important to remain vigilant regarding this rare but catastrophic complication of treatment of retinoblastoma with chemotherapy [137].

VII. CONCLUSIONS

When it is fully understood why RB1 mutations (M1, M2) initiate cancer development specifically in developing retina, the genes and processes that are unbalanced after loss of RB1 (M3 to Mn) will become targets for interventions to prevent the emergence of retinoblastoma in children known to be predisposed. Similarly, knowledge of the genes and growth factors that act independently and cooperatively on retinoblastoma—promoting tumorigenesis, cell cycle progression, differentiation, and programmed cell death (Fig. 1) and their interaction with multidrug-resistance genes (Fig. 3)—will form the basis of novel strategies to cure retinoblastoma.

REFERENCES

1.Godbout R, Dryja TP, Squire J, Gallie BL, Phillips RA. Somatic inactivation of genes on, chromsome 13 is a common event in retinoblastoma. Nature 1983; 304:451–453.

2.Cavenee WK, Hansen MF, Nordenskjold M, et al. Genetic origin of mutations predisposing to retinoblastoma. Science 1985; 228:501–503.

3.Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323:643–646.

4.Squire JA, Gallie BL, Phillips RA. A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma. Hum Genet 1985; 70:291–301.

5.Potluri VR, Helson L, Ellsworth RM, Reid T, Gilbert F. Chromosomal abnormalities in human retinoblastoma. A review. Cancer 1986; 58:663–671.

6.Cepko CL, Austin CP, Yang X, Alexiades M, Ezzeddine D. Cell fate determination in the vertebrate retina. Proc Natl Acad Sci USA 1996; 93:589–595.

7.Belecky-Adams T, Cook B, Adler R. Correlations between terminal mitosis and differentiated fate of retinal precursor cells in vivo and in vitro: Analysis with the ‘‘window-labeling’’ technique. Dev Biol 1996; 178:304–315.

8.Lin LF, Mismer D, Lile JD, et al. Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science 1989; 246:1023–1025.

9.Ezzeddine ZD, Yang X, DeChiara T, Yancopoulos G, Cepko CL. Postmitotic cells fated to become rod photoreceptors can be respecified by CNTF treatment of the retina. Development 1997; 124:1055–1067.

10.Robanus-Maandag E, Dekker M, van der Valk M, et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 1998; 12:1599–1609.

11.Wells W. The Rb pretenders: Report from the American Association for Cancer Research, San Francisco, 2002. J Cell Biol 2002; 157:549.

12.Clarke AR, Maandag ER, vanRoon M, et al. Requirement for a functional Rb-1 gene in murine development. Science 1992; 359:328–330.

13.Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an Rb mutation in the mouse. Science 1992; 359:295–300.

14.Lee EY-HP, Chang C-Y, Hu N, et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Science 1992; 359:288–294.

15.Morgenbesser SD, Williams BO, Jacks T, DePinho RA. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 1994; 371:72–74.

16.Zacksenhaus E, Jiang Z, Chung D, Marth JD, Phillips RA, Gallie BL. pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis. Genes Dev 1996; 10:3051–3064.

17.Maandag EC, van der Valk M, Vlaar M, et al. Developmental rescue of an embryoniclethal mutation in the retinoblastoma gene in chimeric mice. EMBO J 1994; 13:4260– 4268.

18.Williams BO, Schmitt EM, Remington L, et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J 1994; 13:4251–4259.

19.Hu N, Gutsmann A, Herbert DC, Bradley A, Lee W-H, Lee EY-HP. Heterozygous Rb- 1D20/ þ mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 1994; 9:1021–1027.

20.Lee M-H, Williams BO, Mulligan G, et al. Targeted disruption of p107: Functional overlap between p107 and Rb. Genes Dev 1996; 10:1621–1632.

21.Cobrinik D, Lee M-H, Hannon G, et al. Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev 1996; 10:1633–1644.

22.Robanus-Maandag E, Dekker M, Van der Valk M, et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 1998; 12:1599–1609.

23.Windle JJ, Albert DM, O’Brien JM, et al. Retinoblastoma in transgenic mice. Nature 1990; 343:665–669.

24.al-Ubaidi MR, Font RL, Quiambao AB, et al. Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter. J Cell Biol 1992; 119:1681–1687.

25.Howes KA, Lasudry JG, Albert DM, Windle JJ. Photoreceptor cell tumors in transgenic mice. Invest Ophthalmol Vis Sci 1994; 35:342–351.

26.Marcus DM, Lasudry JG, Carpenter JL, et al. Trilateral tumors in four different lines of transgenic mice expressing SV40 T-antigen. Invest Ophthalmol Vis Sci 1996; 37:392– 396.

27.Cepko CL. The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr Opin Neurobiol 1999; 9:37–46.

28.Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: Spontaneous regression of retinoblastoma or benign manisfestation of the mutation? Br J Cancer 1982; 45:513–521.

29.Margo C, Hidayat LCA, Kopelman J, Zimmerman LE. Retinocytoma. A benign variant of retinoblastoma. Arch Ophthalmol 1983; 101:1519–1531.

30.Gallie BL, Phillips RA, Ellsworth RM, Abramson DH. Significance of retinoma and phthisis bulbi for retinoblastoma. Ophthalmology 1982; 89:1393–1399.

31.Aaby AA, Price RL, Zakov ZN. Spontaneously regressing retinoblastomas, retinoma or retinoblastoma group 0. Am J Ophthalmol 1983; 96:315–320.

32.Eagle RCJ, Shields JA, Donoso L, Milner RS. Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 1989; 96:1389–1395.

33.Alio´ J, Luden˜a M, Millan A, Caballero V, Guinaldo V. Ultrastructural study of a retinoma by intraocular fine-needle aspiration biopsy. Ophthalmologica 1988; 196:192– 199.

34.Balmer A, Munier F, Gailloud C. Retinoma and phtisis bulbi: Benign expression of retinoblastoma. Klin Monatsbl Augenheilkd 1992; 200:436–439.

35.Balmer A, Munier F, Gailloud C. Retinoma. Case studies. Ophthalm Paediatr Genet 1991; 12:131–137.

36.Keith CG, Webb GC. Retinoblastoma and retinoma occurring in a child with a translocation and deletion of the long arm of chromosome 13. Arch Ophthalmol 1985; 103:941–944.

37.Rychener RO. Retinoblastoma in the adult. Trans Am Ophthalmol Soc 1948; 46:318– 326.

38.Balmer A, Munier F, Gailloud C. Retinoma. Case Studies. Ophthalm Paediatr Genet 1991; 12:131–137.

39.Lueder GT, Heon E, Gallie BL. Retinoma associated with vitreous seeding. Am J Ophthalmol 1995; 119:522–523.

40.Gallie BL, Campbell C, Devlin H, Duckett A, Squire JA. Developmental basis of retinal-specific induction of cancer by RB mutation. Cancer Res 1999; 59:1731s–1735s.

41.Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323:643–646.

42.Dunn JM, Phillips RA, Zhu X, Becker AJ, Gallie BL. Mutations in the RB1 gene and their effects on transcription. Mol Cell Biol 1989; 9:4594–4602.

43.Harbour JW. Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening. Ophthalmology 1998; 105:1442–1447.

44.Lohmann DR. RB1 gene mutations in retinoblastoma. Hum Mutat 1999; 14:283–288.

45.Zeschnigk M, Lohmann D, Horsthemke B. A PCR test for the detection of hypermethylated alleles at the retinoblastoma locus (letter). J Med Genet 1999; 36:793–794.

45a. Richter S, Vandezande K, Chen N, Zhang K, Sutherland J, Anderson J, Han L, Panton R, Branco P, Gallie B. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet 2003; 72:253–269.

46.Rideout WM, 3rd, Coetzee GA, Olumi AF, Jones PA. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 1990; 249:1288–1290.

47.Schmutte C, Jones PA. Involvement of DNA methylation in human carcinogenesis. Biol Chem 1998; 379:377–388.

48.Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12:2245– 2262.

49.Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 1993; 85:1121–1128.

50.Noorani HZ, Khan HN, Gallie BL, Detsky AS. Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet 1996; 59:301–307.

51.Zhu X, Dunn JM, Goddard AD, et al. Preferential germline mutation of the paternal allele in retinoblastoma. Nature 1989; 340:312–313.

52.Bunin GR, Petrakova A, Meadows AT, et al. Occupations of parents of children with retinoblastoma: A report from the Children’s Cancer Study Group. Cancer Res 1990; 50:7129–7133.

53.Bunin GR, Meadows AT, Emanuel BS, Buckley JD, Woods WG, Hammond GD. Preand postconception factors associated with sporadic heritable and nonheritable retinoblastoma. Cancer Res 1989; 49:5730–5735.

54.Munier FL. Evidence of somatic and germinal mosaicism in pseudo-low penetrance hereditary retinoblastoma by constitutional and single-sperm mutation analysis. Am J Hum Genet 1998; 63:1903–1908.

55.Sippel KC, Fraioli RE, Smith GD, et al. Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 1998; 62:610– 619.

56.Lohmann DR, Brandt B, Ho¨pping W, Passarge E, Horsthemke B. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Hum Genet 1994; 94:349– 354.

57.Otterson GA, Chen W, Coxon AB, Khleif SN, Kaye FJ. Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. Proc Natl Acad Sci USA 1997; 94:12036–12040.

58.Lohmann D, Horsthemke B, Gillessen KG, Stefani FH, Hofler H. Detection of small RB1 gene deletions in retinoblastoma by multiplex PCR and high-resolution gel electrophoresis. Hum Genet 1992; 89:49–53.

59.Onadim A, Hogg A, Baird PN, Cowell JK. Oncogenic point mutation in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype. Proc Natl Acad Sci USA 1992; 89:6177–6181.

60.Kratzke RA, Otterson GA, Hogg A, et al. Partial inactivation of the RB product in a family with incomplete penetrance of familial retinoblastoma and benign retinal tumors. Oncogene 1994; 9:1321–1326.

61.Whitaker LL, Su H, Baskaran R, Knudsen ES, Wang JY. Growth suppression by an E2F-binding-defective retinoblastoma protein (RB): Contribution from the RB C pocket. Mol Cell Biol 1998; 18:4032–4042.

62.Schubert EL, Strong LC, Hansen MF. A splicing mutation in RB1 in low penetrance retinoblastoma. Hum Genet 1997; 100:557–563.

63.Otterson GA, Modi S, Ngugen K, Coxon AB, Kaye FJ. Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families. Am J Hum Genet 1999; 65:1040–1046.

64.Cowell JK, Bia B. A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype. Oncogene 1998; 16:3211–3213.

65.Bremner R, Du DC, Connolly-Wilson MJ, et al. Deletion of RB exons 24 and 25 causes low penetrance retinoblastoma. Am J Hum Genet 1997; 61:556–570.

66.Nevins JR. The Rb/E2F pathway and cancer. Hum Mol Genet 2001; 10:699–703.

67.Orjuela M, Orlow I, Dudas M, et al. Alterations of cell cycle regulators affecting the RB pathway in nonfamilial retinoblastoma. Hum Pathol 2001; 32:537–544.

68.Orjuela M, Castaneda VP, Ridaura C, et al. Presence of human papilloma virus in tumor tissue from children with retinoblastoma: An alternative mechanism for tumor development. Clin Cancer Res 2000; 6:4010–4016.

69.Knudson JAG. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820–823.

70.Mairal A, Pinglier E, Gilbert E, et al. Detection of chromosome imbalances in retinoblastoma by parallel karyotype and CGH analyses. Genes Chromosomes Cancer 2000; 28:370–379.

71.Herzog S, Lohmann DR, Buiting K, et al. Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization. Hum Genet 2001; 108:98–104.

72.Chen D, Gallie BL, Squire JA. Minimal regions of chromosomal imbalance in retinoblastoma detected by comparative genomic hybridization. Cancer Genet Cytogenet 2001; 129:57–63.

73.Guan XY, Fang Y, Sham JS, et al. Recurrent chromosome alterations in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 2000; 29:110–116.

74.Kytola S, Farnebo F, Obara T, et al. Patterns of chromosomal imbalances in parathyroid carcinomas. Am J Pathol 2000; 157:579–586.

75.Zettl A, Strobel P, Wagner K, et al. Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol 2000; 157:257–266.

76.Alers JC, Rochat J, Krijtenburg PJ, et al. Identification of genetic markers for prostatic cancer progression. Lab Invest 2000; 80:931–942.

77.Bergamo NA, Rogatto SR, Poli-Frederico RC, et al. Comparative genomic hybridization analysis detects frequent over-representation of DNA sequences at 3q, 7p, and 8q in head and neck carcinomas. Cancer Genet Cytogenet 2000; 119:48–55.

78.Squire J, Phillips RA, Boyce S, Godbout R, Rogers B, Gallie BL. Isochromosome 6p, a unique chromosomal abnormality in retinoblastoma: Verification by standard staining techniques, new densitometric methods, and somatic cell hybridization. Hum Genet 1984; 66:46–53.

79.Horsthemke B, Greger V, Becher R, Passarge E. Mechanism of i(6p) formation in retinoblastoma tumor cells. Cancer Genet Cytogenet 1989; 37:95–102.

80.Zheng L, Flesken-Nikitin A, Chen P-L, Lee W-H. Deficiency of retinoblastoma gene in mouse embryonic stem cells leads to genetic instability. Cancer Res 2002; 62:2498–2502.

81.Chen D, Pajovic S, Duckett A, Brown VD, Squire JA, Gallie BL. Genomic amplification in retinoblastoma narrowed to 0.6Mb on chromosome 6p containing a kinesin-like gene, RBKIN. Cancer Res 2002; 63:967–971.

82.Bruch J, Schulz WA, Haussler J, et al. Delineation of the 6p22 amplification unit in urinary bladder carcinoma cell lines. Cancer Res 2000; 60:4526–4530.

83.Richter J, Wagner U, Schraml P, et al. Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res 1999; 59:5687–5691.

84.Bando K, Nagai H, Matsumoto S, et al. Identification of a 1-Mb common region at 16q24.1–24.2 deleted in hepatocellular carcinoma. Genes Chromosomes Cancer 2000; 28:38–44.

85.Skirnisdottir S, Eiriksdottir G, Baldursson T, Barkardottir RB, Egilsson V, Ingvarrson S. High frequency of allelic imbalance at chromosome region 16q22–23 in human breast cancer: Correlation with high PgR and low S phase. Int J Cancer 1995; 64:112–116.

86.Suzuki H, Komiya A, Emi M, et al. Three distinct commonly deleted regions of chromosome arm 16q in human primary and metastatic prostate cancers. Genes Chromosomes Cancer 1996; 17:225–233.

87.Mason JE, Goodfellow PJ, Grundy PE, Skinner MA. 16q loss of heterozygosity and microsatellite instability in Wilms’ tumor. J Pediatr Surg 2000; 35:891–896; discussion 896–897.

88.Braungart E, Schumacher C, Hartmann E, et al. Functional loss of E-cadherin and cadherin-11 alleles on chromosome 16q22 in colonic cancer. J Pathol 1999; 187:530– 534.

89.Kashima T, Kawaguchi J, Takeshita S, et al. Anamolous cadherin expression in osteosarcoma. Possible relationships to metastasis and morphogenesis. Am J Pathol 1999; 155:1549–1555.

90.Zhou R, Skalli O. Identification of cadhere-11 down-regulation as a common response of astrocytoma cells to transforming growth factor-alpha. Differentiation 2000; 66:165– 172.

91.Kawakami M, Staub J, Cliby W, Hartmann L, Smith DI, Shridhar V. Involvement of H-cadherin (CDH13) on 16q in the region of frequent deletion in ovarian cancer. Int J Oncol 1999; 15:715–720.

92.Sato M, Mori Y, Sakurada A, Fujimura S, Horii A. The H-cadherin (CDH13) gene is inactivated in human lung cancer. Hum Genet 1998; 103:96–101.

93.Toyooka KO, Toyooka S, Virmani AK, et al. Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. Cancer Res 2001; 61:4556–4560.

94.Frade JM, Bovolenta P, Rodriguez-Tebar A. Neurotrophins and other growth factors in the generation of retinal neurons. Microsc Res Tech 1999; 45:243–251.

95.Frade JM. Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones. J Cell Sci 2000; 113:1139–1148.

96.Frade JM, Rodriguez-Tebar A, Barde YA. Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 1996; 383:166–168.

97.Chadeneau C, Siegel P, Harley CB, Muller WJ, Bacchetti S. Telomerase activity in normal and malignant murine tissues. Oncogene 1995; 11:893–898.

98.Stewart SA, Weinberg RA. Telomerase and human tumorigenesis. Semin Cancer Biol 2000; 10:399–406.

99.Wynford-Thomas D, Kipling D. Telomerase. Cancer and the knockout mouse. Nature 1997; 389:551–552.

100.Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266:2011–2015.

101.Chadeneau C, Hay K, Hirte HW, Gallinger S, Bacchetti S. Telomerase activity associated with acquisition of malignancy in human colorectal cancer. Cancer Res 1995; 55:2533–2536.

102.Counter CM, Hirte HW, Bacchetti S, Harley CB. Telomerase activity in human ovarian carcinoma. Proc Natl Acad Sci USA 1994; 91:2900–2904.

103.Counter CM, Gupta J, Harley CB, Leber B, Bacchetti S. Telomerase activity in normal leukocytes and in hematologic malignancies. Blood 1995; 85:2315–2320.

104.Gupta J, Han L-P, Wang P, Gallie BL, Bacchetti S. Development of retinoblastoma in the absence of telomerase activity. J Natl Cancer Inst 1996; 88:1152–1157.

105.Doz F, Neuenschwander S, Plantaz D, et al. Etoposide and carboplatin in extraocular retinoblastoma: A study by the Socie´te´Franc¸aise d’Oncologie Pe´diatrique. J Clin Oncol 1995; 13:902–909.

106.Namouni F, Doz F, Tanguy ML, et al. High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: A SFOP and SFGM study. Eur J Cancer 1997; 33:2368–2375.

107.Lehnert M. Clinical multidrug resistance in cancer: a multifactorial problem. Eur J Cancer 1996; 32A:912–920.

108.Chan HSL, Grogan TM, DeBoer G, Haddad G, Gallie BL, Ling V. Diagnosis and reversal of multidrug resistance in paediatric cancers. Eur J Cancer 1996; 32A:1051– 1061.

109.Gerlach JH, Kartner N, Bell DR, Ling V. Multidrug resistance. Cancer Surveys 1986; 5:25–46.

110.Gerlach JH, Endicott JA, Juranka PF, et al. Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature 1986; 324:485–489.

111.Fojo AT, Whang-Peng J, Gottesman MM, Pastan I. Amplification of DNA sequences in human multidrug-resistant KB carcinoma cells. Proc Natl Acad Sci USA 1985; 82:7661–7665.

112.Goldstein LJ, Galski H, Fojo AT, et al. Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 1989; 81:116–124.

113.Weinstein RS, Kuszak JR, Kluskens LF, Coon JS. P-glycoproteins in pathology: The multidrug resistance gene family in humans. Hum Pathol 1990; 21:34–48.

114.Gamelin E, Mertins SD, Regis JT, et al. Intrinsic drug resistance in primary and metastatic renal cell carcinoma. J Urol 1999; 162:217–224.

115.Pirker R, Wallner J, Geissler K, et al. MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst 1991; 83:708–712.

116.Campos L, Guyotat D, Jaffar C, Solary E, Archimbaud E, Treille D. Correlation of MDR1/P-170 expression with daunorubicin uptake and sensitivity of leukemic progenitors in acute myeloid leukemia. Eur J Haematol 1992; 48:254–258.

117.Dalton WS, Grogan TM, Rybski JA, et al. Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: Association with level of drug resistance and drug accumulation. Blood 1989; 73:747–752.

118.Miller TP, Grogan TM, Dalton WS, Spier CM, Scheper RJ, Salmon SE. P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil. J Clin Oncol 1991; 9:17–24.

119.Goasguen JE, Dossot JM, Fardel O, et al. Expression of the multidrug resistanceassociated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: Prognostic implications. Blood 1993; 81:2394–2398.

120.Bourhis J, Goldstein LJ, Riou G, Pastan I, Gottesman MM, Benard J. Expression of a human multidrug resistance gene in ovarian carcinomas. Cancer Res 1989; 49:5062– 5065.

121.Chan HSL, Thorner PS, Haddad G, Ling V. Immunohistochemical detection of P- glycoprotein: Prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol 1990; 8:689–704.

122.Chan HSL, Thorner PS, Haddad G, Gallie BL. Multidrug-resistant phenotype in retinoblastoma correlates with P-glycoprotein expression. Ophthalmology 1991; 98:1425–1431.

123.Chan HSL, Haddad G, Thorner PS, et al. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med 1991; 325:1608–1614.

124.Baldini N, Scotlandi K, Barbanti-Bro`dano G, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med 1995; 333:1380–1385.

125.Kang Y-K, Zhan Z, Regis J, et al. Expression of mdr-1 in refractory lymphoma: Quantitation by polymerase chain reaction and validation of the assay. Blood 1995; 86:1515–1524.

126.Chan HSL, Thorner PS, Haddad G, Gallie BL. Effect of chemotherapy on intraocular retinoblastoma. Int J Pediatr Hematol/Oncol 1995; 2:269–281.

127.Chan HSL, Grogan TM, Haddad G, DeBoer G, Ling V. P-Glycoprotein expression: Critical determinant in the response to osteosarcoma chemotherapy. J Natl Cancer Inst 1997; 89:1706–1715.

128.Chan HSL, Lu Y, Grogan TM, et al. Multidrug resistance protein (MRP) expression in retinoblastoma correlates with rare failure of chemotherapy despite cyclosporine for reversal of P-glycoprotein. Cancer Res 1997; 57:2325–2330.

129.Bates SE, Shieh CY, Tsokos M. Expression of mdr-1/P-glycoprotein in human neuroblastoma. Am J Pathol 1991; 139:305–315.

130.Nakagawara A, Kadomatsu K, Sato S, et al. Inverse correlation between expression of multidrug resistance gene and N-myc oncogene in human neuroblastomas. Cancer Res 1990; 50:3043–3047.

131.Niehans GA, Jaszcz W, Brunetto V, et al. Immunohistochemical identification of P- glycoprotein in previously untreated, diffuse large cell and immunoblastic lymphomas. Cancer Res 1992; 52:3768–3775.

132.Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiation. Arch Ophthalmol 1996; 114:1321–1328.

133.Chan HSL, DeBoer G, Thiessen JJ, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res 1996; 2:1499–1508.

134.White L. Chemotherapy in retinoblastoma: Current status and future directions. Am J Pediatr Hematol Oncol 1991; 13:189–201.

135.Murphree AL, Villablanca JG, Deegan WF, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996; 114:1348– 1356.

136.Shields CL, Shields JA, DePotter P, Himelstein BP, Meadows AT. The effect of chemoreduction on retinoblastoma-induced retinal detachment. J Pediatr Ophthalmol Strabismus 1997; 34:165–169.

137.Beck MN, Balmer A, Dessing C, Pica A, Munier F. First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol 2000; 18:2881–2887.

138.Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 2000; 18:12–17.

139.Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction plus focal therapy for retinoblastoma: Factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 2002; 133:657–664.

140.Chan HSL, Canton MD, Gallie BL. Chemosensitivity and multidrug resistance to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res 1989; 9:469–474.

141.Wilson TW, Chan HSL, Moselhy GM, Heydt DD Jr, Frey CM, Gallie BL. Penetration of chemotherapy into vitreous is increased by cryotherapy and cyclosporin in rabbits. Arch Ophthalmol 1996; 114:1390–1395.

142.Stewart PA, Tuor UI. Blood-eye barriers in the rat: Correlation of ultrastructure with function. J Comp Neurol 1994; 340:566–576.

143.Holash JA, Stewart PA. The relationship of astrocyte-like cells to the vessels that contribute to the blood-ocular barriers. Brain Res 1993; 629:218–224.

144.Schlingemann RO, Hofman P, Klooster J, Blaauwgeers HG, Van der Gaag R, Vrensen GF. Ciliary muscle capillaries have blood-tissue barrier characteristics. Exp Cell Res 1998; 66:747–754.

145.Cole SPC, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258:1650–1654.

146.Grant CE, Valdimarsson G, Hipfner DR, Almquist KC, Cole SP, Deeley RG. Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. Cancer Res 1994; 54:357–361.

147.Cole SPC, Sparks KE, Fraser K, et al. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res 1994; 54:5902–5910.

148.Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 1993; 85:1121–1128.

149.Wong FL, Boice JD, Jr., Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 1997; 278:1262–1267.

150.Li FP, Abramson DH, Tarone RE, Kleinerman RA, Fraumeni JF Jr, Boice JD Jr. Hereditary retinoblastoma, lipoma, and second primary cancers. J Natl Cancer Inst 1997; 89:83–84.

151.Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: A possible age effect on radiation-related risk. Ophthalmology 1998; 105:573–579.

152.Imhof SM, Hofman P, Tan KE. Quantification of lacrimal function after D-shaped field irradiation for retinoblastoma. Br J Ophthalmol 1993; 77:482–484.

153.Imhof SM, Mourits MP, Hofman P, et al. Quantification of orbital and mid-facial growth retardation after megavoltage external beam irradiation in children with retinoblastoma. Ophthalmology 1996; 103:263–268.

154.Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 1987; 84:265–269.

155.Cordon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P- glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86:695–698.

156.Drach D, Zhao S, Drach J, et al. Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype. Blood 1992; 80:2729– 2734.

157.Smit JJM, Schinkel AH, Oude Elferink RPJ, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 1993; 75:451–462.

158.Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 1997; 94:4028–4033.

159.Beketic-Oreskovic L, Dura´n GE, Chen G, Dumontet C, Sikic BI. Decreased mutation rate for cellular resistance to doxorubicin and suppression of mdr1 gene activation by the cyclosporin PSC 833. J Natl Cancer Inst 1995; 87:1593–1602.

160.Jette´ L, Beaulieu E, Leclerc JM, Be´liveau R. Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues. Am J Physiol 1996; 270:F756-F765.

161.Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999; 397:530–534.

162.Chan HSL, Heon E, Budning A, Gallie BL. Retinoblastoma shows dose-response to cyclosporine-modulated chemotherapy. Proc Am Assoc Cancer Res 2000; 41:abstr 3866.

163.Kleinerman RA, Tarone RE, Abramson DH, Seddon JM, Li FP, Tucker MA. Hereditary retinoblastoma and risk of lung cancer. J Natl Cancer Inst 2000; 92:2037– 2039.

164.Pedersen-Bjergaard J, Daugaard G, Hansen SW, Philip P, Larsen SO, Rorth M. Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet 1991; 338:359–363.

165.Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 1991; 325:1682–1687.

166.Winick NJ, McKenna RW, Shuster JJ, et al. Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. J Clin Oncol 1993; 11:209–217.

167.Kollmannsberger C, Beyer J, Droz JP, et al. Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 1998; 16:3386–3391.

168.Chen CL, Fuscoe JC, Liu Q, Pui CH, Mahmoud HH, Relling MV. Relationship between cytotoxicity and site-specific DNA recombination after in vitro exposure of leukemia cells to etoposide. J Nat Cancer Inst 1996; 88:1840–1847.

169.Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 1999; 17:569–577.

170.Lum BL, Kaubisch S, Yahanda AM, et al. Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 1992; 10:1635–1642.

171.Yahanda AM, Alder KM, Fisher GA, et al. Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 1992; 10:1624–1634.

172.Travis LB, Holowaty EJ, Bergfeldt K, et al. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med 1999; 340:351–357.

173.Phillips RA, Gill RM, Zacksenhaus E, et al. Why don’t germline mutations in RB1 predispose to leukemia? In: Potter M, Melchers F, eds. Current Topics in Microbiology & Immunology. Vol. 182. Berlin: Springer-Verlag, 1992, pp 485–491.

174.Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986; 53:661–671.

175.Felice MS, Zubizarreta PA, Chantada GL, et al. Acute myeloid leukemia as a second malignancy: Report of 9 pediatric patients in a single institution in Argentina. Med Pediatr Oncol 1998; 30:160–164.