Effect of Imatinib Mesylate (Gleevec) on Anaplastic Thyroid Carcinoma Cell Lines 1

Constantine S. Mitsiades, Despoina Sykoutri, Ciaran McMullan, Vassiliki Poulaki and Nicholas Mitsiades

Department of Medical Oncology (C.S.M., D.S., C.M., N.M.), Dana Farber Cancer Institute, Harvard Medical School, Boston Massachusetts 02115; and Angiogenesis Laboratory (V.P.), Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114

To the editor:

In their recent article in JCEM, Podtcheko et al. (1) reported that the tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) exerts antiproliferative activity against anaplastic thyroid carcinoma cell lines in vitro by targeting the kinase c-Abl. They concluded that anaplastic thyroid carcinomas overexpress c-Abl and that STI571 may hold promise for the treatment of patients with anaplastic thyroid carcinoma.

The only kinases inhibited by imatinib at submicromolar concentrations are c-KIT, c-ABL, the ABL-related gene (ARG), the platelet-derived growth factor receptors (PDGF-R){alpha} and ß, and their oncogenic fusion versions (BCR-ABL and FIP1L1-PDGFR{alpha}). The efficacy of STI571 in the clinical treatment of chronic myelogenous leukemia (CML) lies in the fact that the clinically achievable levels of 1 µM correspond to or exceed the IC90 concentration for both the tyrosine kinase activity of Abl and the antitumor effect of STI571 against CML cells in vitro (the IC50 for the antitumor activity of STI571 against BCR/ABL-expressing cell lines is 0.05–0.3 µM; Ref.2). Therefore, the IC50 values (5.9 and 7.8 µM) reported by Podtcheko et al. for the anaplastic thyroid carcinoma cell lines are extremely high. For comparison, Podtcheko et al. (1) treated the thyroid carcinoma cell lines ARO and FRO with a 10-µM concentration of STI571 for 48 h, and they found that the proportion of cells in G2/M phase in the ARO cell line increased from 3.78% in controls to 9.28% in treated cells, and the proportion of S phase cells in the FRO cell line increased from 43% in controls to 54% in treated cells (see Fig. 5), which they interpret as growth arrest. No apoptotic (sub-G1 cells) were found. This effect is miniscule compared with the eradicating effect of STI571 on CML cell lines under the same conditions (complete inhibition of proliferation, accompanied by induction of massive apoptosis; Ref.2).

The authors claim that the IC50 values they report for STI571 in thyroid carcinoma cell lines are clinically achievable. Actually, in the CML clinical trials, once-daily oral administration of 400 mg of STI571 resulted in a mean maximal concentration of 4.6 µM and mean plasma trough concentration of 1.46 µM (3). These levels exceeded the IC50 (and even IC90) for inhibiting BCR-ABL enzymatic activity and proliferation of CML cell lines positive for BCR-ABL in vitro. However, a concentration of STI571 in the range of 10 µM, used by Podtcheko et al. (1), cannot be sustained for a period of time sufficient to induce the biological effect that the authors attribute to c-Abl inhibition in thyroid carcinoma cells, without resulting in toxic side effects.

Indeed, although STI571 is considered safe, its clinical use is not devoid of dose-limiting toxicity. Conventional doses of STI571 induce side effects, such as edema, nausea/vomiting, muscle cramps, neutropenia, thrombocytopenia, fever, liver toxicity, arthralgia, and exanthema/rash (4). This clearly indicates that the currently administered doses of STI571 cannot be raised further and that patients with malignancies that exhibit in vitro sensitivity much lower than that of CML cell lines are unlikely to obtain clinical benefit from Gleevec.

Moreover, the IC50 of STI571 for the enzymatic activity of purified c-Abl and Bcr-Abl is 0.25 µM (5, 6), i.e. very close to the IC50 for its antitumor effect against CML cells. Therefore, if c-Abl inhibition was responsible for the reported effect of STI571 on anaplastic thyroid carcinoma cell lines, it would be expected that the IC50 of STI571 against these cells would be similar, i.e. approximately 40 times lower than that reported by Podtcheko et al. This raises serious concerns for their conclusion that c-Abl is the target of STI571 in their model. Indeed, at the concentration of 10 µM used by Podtcheko et al., imatinib loses specificity (7), because it inhibits other kinases as well, such as lck (5).

These considerations clearly indicate that 1) the reported effect of STI571 on anaplastic thyroid carcinoma cell lines cannot be attributed to c-Abl inhibition alone, and 2) that it is not of a sufficient magnitude to be relevant to the in vivo setting of treatment of patients with anaplastic carcinoma. Clearly, more studies are necessary before the use of STI571 is advocated for clinical trials in patients with anaplastic thyroid carcinoma.

Footnotes

1 Address correspondence to: Nicholas Mitsiades, M.D., Ph.D., Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Mayer Building M555, Boston Massachusetts 02115. E-mail: mitsiades{at}netscape.net. Back

Received June 4, 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. 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]
  3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL 2001 Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037[Abstract/Free Full Text]
  4. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O’Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E, The International STICMLSG 2002 Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652[Abstract/Free Full Text]
  5. Buchdunger E, Matter A, Druker BJ 2001 Bcr-Abl inhibition as a modality of CML therapeutics. Biochim Biophys Acta 1551:M11–M18
  6. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB 1996 Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566[Medline]
  7. Druker BJ 2002 Taking aim at Ewing’s sarcoma: is KIT a target and will imatinib work? J Natl Cancer Inst 94:1660–1661[Free Full Text]




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