Effect of telomere and telomerase interactive agents on human tumor and normal cell lines

Sun Young Rha, Elzbieta Izbicka, Richard Lawrence, Karen Davidson, Daekyu Sun, Mary Pat Moyer, G. David Roodman, Lawrence Hurley, Daniel Von Hoff

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Shortening of telomeres along with an up-regulation of telomerase is implicated in the immortality of tumor cells. Targeting either telomeres or telomerase with specific compounds has been proposed as an anticancer strategy. Because telomerase activity and telomeres are found in normal cells, telomere or telomerase targeting agents could induce side effects in normal tissues. We evaluated the effects of telomere and telomerase interactive agents in human tumor and normal cell lines to try to determine the potential side effects those agents might induce in patients. Toxicity of the G-quadruplex interactive porphyrins (TMPyP4, TMPyP2) and azidothymidine (AZT) were tested using a cell-counting technique against normal human cell lines (CRL-2115 and CRL-2120, fibroblasts; NHEK-Ad, adult keratinocytes; CCL- 241, small intestinal cells; NCM 460, colonic mucosal epithelial cells) and human tumor cell lines (MDA-MB 231 and Hs 578T, breast cancer; SK-N-FI, neuroblastoma; HeLa, cervix cancer; MIA PaCa-2, pancreatic cancer; HT-29 and HCT-116, colon cancer; DU 145, prostatic cancer cell line). Telomerase activity of these cell lines was measured by a non-PCR-based conventional assay. The effects of TMPyP2, TMPyP4, and AZT were also evaluated against normal human bone marrow specimens, using a granulocyte-macrophage colony- forming assay (CFU-GM). AZT showed very low cytotoxic effects against normal and tumor cell lines, with the IC50 values above 200 μM. The IC50 values for TMPyP2 and TMPyP4 in normal human cell lines were in the range of 2.9- 48.3 μM and 1.7-15.5 μM, respectively, whereas in tumor cell lines the IC50 values were 11.4-53 μM and 9.0-28.2 μM, respectively. Within the tissue types, keratinocytes were more sensitive to TMPyP4 than fibroblasts, and small intestinal cells were more sensitive than colonic mucosal epithelial cells. The IC50 for TMPyP2 and TMPyP4 in the normal marrow colony-forming assays were 19.3 ± 5.1 μM and 47.9 ± 1.0 μM, respectively. In conclusion, the in vitro cytotoxicity of the telomere interactive agent TMPyP4 is comparable in human tumor and normal cell lines, which indicates that TMPyP4 could have effects on normal tissues.

Original languageEnglish (US)
Pages (from-to)987-993
Number of pages7
JournalClinical Cancer Research
Volume6
Issue number3
StatePublished - Mar 2000
Externally publishedYes

Fingerprint

Telomerase
Telomere
Tumor Cell Line
Inhibitory Concentration 50
Zidovudine
Cell Line
Keratinocytes
Fibroblasts
Bone Marrow
Epithelial Cells
G-Quadruplexes
Telomere Shortening
Granulocyte-Macrophage Progenitor Cells
Porphyrins
tetra(4-N-methylpyridyl)porphine
Neuroblastoma
Pancreatic Neoplasms
Granulocytes
Uterine Cervical Neoplasms
Colonic Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rha, S. Y., Izbicka, E., Lawrence, R., Davidson, K., Sun, D., Moyer, M. P., ... Von Hoff, D. (2000). Effect of telomere and telomerase interactive agents on human tumor and normal cell lines. Clinical Cancer Research, 6(3), 987-993.

Effect of telomere and telomerase interactive agents on human tumor and normal cell lines. / Rha, Sun Young; Izbicka, Elzbieta; Lawrence, Richard; Davidson, Karen; Sun, Daekyu; Moyer, Mary Pat; Roodman, G. David; Hurley, Lawrence; Von Hoff, Daniel.

In: Clinical Cancer Research, Vol. 6, No. 3, 03.2000, p. 987-993.

Research output: Contribution to journalArticle

Rha, SY, Izbicka, E, Lawrence, R, Davidson, K, Sun, D, Moyer, MP, Roodman, GD, Hurley, L & Von Hoff, D 2000, 'Effect of telomere and telomerase interactive agents on human tumor and normal cell lines', Clinical Cancer Research, vol. 6, no. 3, pp. 987-993.
Rha SY, Izbicka E, Lawrence R, Davidson K, Sun D, Moyer MP et al. Effect of telomere and telomerase interactive agents on human tumor and normal cell lines. Clinical Cancer Research. 2000 Mar;6(3):987-993.
Rha, Sun Young ; Izbicka, Elzbieta ; Lawrence, Richard ; Davidson, Karen ; Sun, Daekyu ; Moyer, Mary Pat ; Roodman, G. David ; Hurley, Lawrence ; Von Hoff, Daniel. / Effect of telomere and telomerase interactive agents on human tumor and normal cell lines. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 3. pp. 987-993.
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