Authors’ Response: Effect of Imatinib Mesylate (Gleevec) on Anaplastic Thyroid Carcinoma Cell Lines

Alexei Podtcheko, Akira Ohtsuru, Hiroyuki Namba, Vladimir Saenko and Shunichi Yamashita

Department of Molecular Medicine (A.P., A.O., H.N., S.Y.), International Health and Radiation Research (V.S., S.Y.), Nagasaki University, Graduate School of Biomedical Sciences; and Takashi Nagai International Hibakusha Medical Center (A.O., S.Y.), Nagasaki University Hospital, Nagasaki 852-8501, Japan

To the editor:

We appreciate the comments of Mitsiades and associates about our recent paper in JCEM (1). Mitsiades et al. raise two main relevant questions regarding the potential molecular targets in our models and the feasibility to achieve an appropriate concentration of the drug in a patient’s bloodstream for clinical treatment.

We agree with Mitsiades et al. that STI571 in concentrations exceeding 1 µM displays weaker selectivity and may influence the activity of some kinases other than those regarded as its specific targets. Recent studies have demonstrated that STI571 at concentrations under 10 µM could down-regulate ß-catenin signaling pathway (2). This signaling has been shown to contribute to the highly aggressive behavior of anaplastic thyroid carcinoma (ATC) (3). Our recent findings also suggest that STI571, in concentrations more than 5 µM, most likely indirectly, significantly inhibits intracellular basal activity of JNK (c-Jun NH2-terminal kinase) (Podtcheko, A., unpublished data), which, as follows from our previous studies, associates with survival or transformation of human thyroid cells (4). Thus, the in vitro net effect of relatively high concentrations of STI571 used in our experiments may indeed be attributable to the alterations of the activity of a variety of factors superimposed on the inhibition of a canonic STI571 target, c-ABL, whose enzymatic activity was attenuated in time- and dose-dependent manner in the drug-treated cultures.

As for the clinically achievable doses of the drug, it is worth noting that STI571 has been approved by USFDA (United States Food and Drug Administration) for the treatment of malignant gastrointestinal stromal tumors, with recommended doses of 400 or 600 mg daily. Our selection of the drug concentration range in experiments was largely based on the results of a study performed by Mauro and Druker (5) in which they observed no dose-limiting toxicity in patients with chronic myelogenous leukemia after a once-daily dose of 600 mg of Gleevec. According to their report, mean plasma concentration of STI571 reached at steady state was 3.9 µg/ml (7.8 µM), which is quite comparable with IC50 values determined in our work for ATC cells. Additionally, there are no strict regulations of the evaluation of IC50 of STI571 (which actually needed); in different studies, time of exposure to STI571 for estimation of IC50 varies from 48 h to 11 d (6). We used the shortest duration of the treatment, 48 h, whereas our unpublished data suggest that with increasing exposure time growth inhibitory effect of the same dose of the STI571 can be more prominent. Furthermore, IC50 values (1.2–4.2 µM) for chronic myelogenous leukemia cell lines obtained from patients and tested in the presence of growth factors (7) were similar to those for ATC, suggesting that in vitro IC50 data could be modified by culture conditions. Therefore, the question of whether it is possible to achieve effective cytostatic concentration of STI571 in human thyroid carcinoma tissue would clearly require further investigations to be conducted with all possible cautions mandatory for clinical trials.

Taking into account that anaplastic thyroid cancer is one of the most aggressive human malignancies, which leaves the patient virtually no chance of a long-term survival, any reasonable modality should not be discounted as a potential means of the treatment.

Footnotes

Address correspondence to: Akira Ohtsuru, M.D., Ph.D., Takashi Nagai International Hibakusha Medical Center, Nagasaki University Hospital, Sakamoto 1-7-1, Nagasaki 852-8501, Japan. E-mail: ohtsuru{at}net.nagasaki-u.ac.jp.

Received July 12, 2003.

References

  1. Podtcheko A, Ohtsuru A, Tsuda S, Namba H, Saenko V, Nakashima M, Mitsutake N, Kanda S, Kurebayashi J, Yamashita S 2003 The selective tyrosine kinase inhibitor, STI571, inhibits growth of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 88:1889–1896[Abstract/Free Full Text]
  2. Zhou L, An N, Haydon RC, Zhou Q, Cheng H, Peng Y, Jiang W, Luu HH, Vanichakarn P, Szatkowski JP, Park JY, Breyer B, He TC 2002 Tyrosine kinase inhibitor STI571/Gleevec down-regulates the ß-catenin signaling activity. Cancer Lett 193:161–170
  3. Garcia-Rostan G, Tallini G, Herrero A, D’Aquila TG, Carcangiu ML, Rimm DL 1999 Frequent mutation and nuclear localization of ß-catenin in anaplastic thyroid carcinoma. Cancer Res 59:1811–1815[Abstract/Free Full Text]
  4. Shklyaev SS, Namba H, Mitsutake N, Alipov G, Nagayama Y, Maeda S, Ohtsuru A, Tsubouchi H, Yamashita S 2001 Transient activation of c-Jun NH2-terminal kinase by growth factors influences survival but not apoptosis of human thyrocytes. Thyroid 11:629–636[CrossRef][Medline]
  5. Mauro MJ, Druker BJ 2001 STI571: targeting BCR-ABL as therapy for CML. Oncologist 6:233–238[Abstract/Free Full Text]
  6. Kilic T, Alberta JA, Zdunek PR, Acar M, Iannarelli P, O’Reilly T, Buchdunger E, Black PM, Stiles CD 2000 Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res 15:5143–5150
  7. Gambacorti-Passerini C, le Coutre P, Mologni L, Fanelli M, Bertazzoli C, Marchesi E, Di Nicola M, Biondi A, Corneo GM, Belotti D, Pogliani E, Lydon NB 1997 Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 23:380–394[CrossRef][Medline]




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