This study evaluated the telomere length changes (ΔTL) of peripheral blood mononuclear cells before and after repetitive standard-dose nonmyeloablative chemotherapy and the association of ΔTL with treatment response and myelosuppression severity. TL was measured with Southern blot analysis in 32 solid-cancer patients without bone marrow metastasis. The mean TL before chemotherapy (t0 TL) and after the 2nd (t1 TL), 4th (t2 TL) and 6th cycle (t3 TL) was 8.49, 8.33, 8.08 and 8.10 kb, respectively. TL became significantly decreased after 4 (p = 0.005) and 6 (p = 0.026) cycles of chemotherapy. The mean value of ΔTL before and after completion of chemotherapy (t0 TL – t3 TL) was 0.46 kb. ΔTL has a significant correlation with good treatment response (r = 0.448, p = 0.005) and the frequency of severe neutropenia (r = 0.417, p < 0.05). Consequently, TL of peripheral blood mononuclear cells was decreased by the repetitive nonmyeloablative standard-dose chemotherapy in solid-cancer patients without bone marrow metastasis, and ΔTL was associated with good treatment response and neutropenia severity.

Keywords:
Cancer chemotherapy, nonmyeloablative, Neutropenia, Telomere length
1.
Blackburn EH: Structure and function of telomeres. Nature 1991;350:569–573.
2.
Zakian VA: Telomeres: beginning to understand the end. Science 1995;270:1601–1607.
3.
Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu J-R: A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 1988;85:6622–6626.
4.
Rhyu MS: Telomeres, telomerase, and immortality. J Natl Cancer Inst 1995;87:884–894.
5.
Frenck RW Jr, Blackburn EH, Shannon KM: The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA 1998;95:5607–5610.
6.
Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC: Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990;346:866–868.
7.
Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM: Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 1994;91:9857–9860.
8.
Akiyama M, Asai O, Kuraishi Y, Urashima M, Hoshi Y, Sakamaki H, Yabe H, Furukawa T, Yamada O, Mizoguchi H, Yamada H: Shortening of telomeres in recipients of both autologous and allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2000;25:441–447.
9.
Allsopp RC, Cheshier S, Weissman IL: Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med 2001;193:917–924.
10.
Lee J, Kook H, Chung I, Kim H, Park M, Kim C, Nah J, Hwang T: Telomere length changes in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 1999;24:411–415.
11.
Mathioudakis G, Storb R, McSweeney PA, Torok-Storb B, Lansdorp PM, Brummendorf TH, Gass MJ, Bryant EM, Storek J, Flowers MED, Gooley T, Nash RA: Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients. Blood 2000;96:3991–3994.
12.
Ricca I, Compagno M, Ladetto M, Rocci A, Dell’Aquila M, Omede P, De Marco F, D’Antico S, Caracciolo D, Ferrero D, Carlo-Stella C, Tarella C: Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF. Leukemia 2005;19:644–651.
13.
Rufer N, Brummendorf TH, Chapuis B, Helg C, Lansdorp PM, Roosnek E: Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood 2001;97:575–577.
14.
Lee JJ, Nam CE, Cho SH, Park KS, Chung IJ, Kim HJ: Telomere length shortening in non-Hodgkin’s lymphoma patients undergoing chemotherapy. Ann Hematol 2003;82:492–495.
15.
Schroder CP, Wisman GB, de Jong S, van der Graaf WT, Ruiters MH, Mulder NH, de Leij LF, van der Zee AG, de Vries EG: Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation. Br J Cancer 2001;84:1348–1353.
16.
Lansdorp PM: Self-renewal of stem cells. Biol Blood Marrow Transplant 1997;3:171–178.
17.
Ball SE, Gibson FM, Rizzo S, Tooze JA, Marsh JCW, Gordon-Smith EC: Progressive telomere shortening in aplastic anemia. Blood 1998;91:3582–3592.
18.
Ohyashiki JH, Iwama H, Yahata N, Ando K, Hayashi S, Shay JW, Ohyashiki K: Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes. Clin Cancer Res 1999;5:1155–1160.
19.
Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA: Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999;96:701–712.
20.
Engelhardt M, Ozkaynak MF, Drullinsky P, Sandoval C, Tugal O, Jayabose S, Moore MA: Telomerase activity and telomere length in pediatric patients with malignancies undergoing chemotherapy. Leukemia 1998;12:13–24.
21.
Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 1981;47:207–214.
22.
Wynn RF, Cross MA, Hatton C, Will AM, Lashford LS, Dexter TM, Testa NG: Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants. Lancet 1998;351:178–181.
23.
Beeharry N, Broccoli D: Telomere dynamics in response to chemotherapy. Curr Mol Med 2005;5:187–196.
24.
Chu E, DeVita VT: Principles governing the use of chemotherapy; in DeVita VT, Hellman S, Rosenberg SA: Cancer Principles and Practice of Oncology, ed 7. Philadelphia, Lippincott, Williams & Wilkins, 2005, vol 1, pp 295–306.
25.
Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD: Obesity, cigarette smoking, and telomere length in women. Lancet 2005;366:662–664.
26.
Ramirez R, Carracedo J, Soriano S, Jimenez R, Martin-Malo A, Rodriguez M, Blasco M, Aljama P: Stress-induced premature senescence in mononuclear cells from patients on long-term hemodialysis. Am J Kidney Dis 2005;45:353–359.
27.
Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM: Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 2004;101:17312–17315.
28.
Karin M, Lawrence T, Nizet V: Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006;124:823–835.
29.
Adamson DJ, King DJ, Haites NE: Significant telomere shortening in childhood leukemia. Cancer Genet Cytogenet 1992;61:204–206.
30.
Bisoffi M, Heaphy CM, Griffith JK: Telomeres: prognostic markers for solid tumors. Int J Cancer 2006;119:2255–2260.
31.
Griffith JK, Bryant JE, Fordyce CA, Gilliland FD, Joste NE, Moyzis RK: Reduced telomere DNA content is correlated with genomic instability and metastasis in invasive human breast carcinoma. Breast Cancer Res Treat 1999;54:59–64.
32.
Garcia-Aranda C, de Juan C, Diaz-Lopez A, Sanchez-Pernaute A, Torres AJ, Diaz-Rubio E, Balibrea JL, Benito M, Iniesta P: Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma. Cancer 2006;106:541–551.
33.
Ohali A, Avigad S, Ash S, Goshen Y, Luria D, Feinmesser M, Zaizov R, Yaniv I: Telomere length is a prognostic factor in neuroblastoma. Cancer 2006;107:1391–1399.
34.
Franco S, Ozkaynak MF, Sandoval C, Tugal O, Jayabose S, Engelhardt M, Moore MA: Telomere dynamics in childhood leukemia and solid tumors: a follow-up study. Leukemia 2003;17:401–410.
35.
Skipper HE: Kinetics of mammary tumor cell growth and implications for therapy. Cancer 1971;28:1479–1499.
36.
Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 1984;2:1281–1288.
37.
Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 1987;5:756–767.
38.
Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR, Ballow AC, Frei E, Henderson IC: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330:1253–1259.
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2007
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