- Email: [email protected]
Re: “Inhibition of medullary thyroid carcinoma (MTC) cell proliferation and RET phosphorylation by tyrosine kinase inhibitors”
Letters to the Editors Re: ‘‘Surgical education: In need of a shift in paradigm’’ To the Editors: The logical place to begin implementing ‘‘. . .major Flexnerian change in the way we train surgeons’’ is the weekly surgical morbidity and mortality conference. This conference has never reached its full educational potential. It is time that it does. Why should the weekly surgical morbidity and mortality conference become the flashpoint for the educational changes deemed so necessary by Dr Silen? Consider the following: 1. The conference is the only time during the week during which staff and residents assemble for a formal interactive session. 2. The conference is the only time in which the spectrum of departmental clinical knowledge is presented in a format that allows discussion of surgical fact, principle, and folklore. 3. The conference will aid staff in developing the skills needed to correct the deficiencies so clearly pointed out by Dr Silen. 4. The conference can become a forum for educational change. 5. The conference addresses the pressing issue of error and complication reduction in surgery. 6. The conference is the ideal vehicle for fostering Dr Silen’s ‘‘small team’’ approach. 7. The conference is an existing mechanism currently free of the need for high-level funding. It exists as part of the cultural heritage of most departments of surgery. 8. The well-moderated, well-attended, and wellplanned conference can serve as a medical student recruitment tool. 9. The conference can generate a year-long surgical curriculum for the entire department of surgery. 10. The increasing educational value realized by redesigning this conference will counteract the deleterious educational effects of mandated work-hour restrictions. When Abraham Flexner filed his report in 1910, he recommended the implementation of ‘‘simple measures’’ to solve the problems of medical education.1 Redefining the surgical morbidity and mortality conference is one such measure. Such changes are currently underway in many progressive departments of surgery.
Leo A. Gordon, MD, FACS Associate Director of Surgical Education Department of Surgery Cedars-Sinai Medical Center 8700 Beverly Blvd, Ste 8215 Los Angeles, CA 90048
240 SURGERY
References 1. Flexner A. Medical education in the United States and Canada—A report to the Carnegie Foundation for the Advancement of Teaching. New York: The Carnegie Foundation for the Advancement of Teaching; 1910. 50. doi:10.1016/j.surg.2003.11.003
Re: ‘‘Inhibition of medullary thyroid carcinoma (MTC) cell proliferation and RET phosphorylation by tyrosine kinase inhibitors’’ To the Editors: An important target for cancer research is the search for efficient anticancer drugs. Recently, tyrosine kinase inhibitors, in particular Gleevec, also known as Glivec, STI1571, and CGP57148B, have been used very successfully in the clinical management of chronic myelogenous leukemias and in gastrointestinal stromal tumors. The targets of Gleevec in these cancers are BCR-ABL and CKIT, both receptor tyrosine kinases. The success of Gleevec prompted many groups to investigate it in relation to other tumors expressing receptor tyrosine kinases similar to BCR-ABL or C-KIT. An obvious target is RET, a tyrosine kinase receptor often mutated in medullary thyroid carcinoma (MTC) and pheochromocytomas. In the December 2002 issue of this journal, Cohen, Hussain, and Moley described the use of Gleevec to inhibit RET activity in a cell line derived from an MTC.1 The authors reported that Gleevec inhibits both proliferation of this MTC cell line and RET tyrosine phosphorylation. The paper raises several questions that we would like to address in this letter. The first concerns the interpretation of Fig 1, which shows the effect of Gleevec on the tyrosine phosphorylation status of the RET receptor. The authors conclude from the upper panel of the figure that loss of tyrosine kinase activity correlates with an increase in the concentration of Gleevec. Indeed, the Western blot analysis shows a Gleevec concentration-dependent decrease in tyrosine-phosphorylated RET. However, when the same blot is probed again with a RET antibody, this amount also decreases with increasing concentrations of Gleevec. Therefore, a more correct conclusion would be that less RET is immunoprecipitated from cells treated with increasing Gleevec concentrations and, therefore, less tyrosine-phosphorylated RET is detected. Without a blot analysis of total cell lysates before immunoprecipitation, it is impossible to conclude how Gleevec treatment results in reduced RET protein levels. A second question concerns the fairly high concentration of Gleevec used for the cell proliferation studies. The data would be more convincing if the authors had tested these concentrations on several control cell lines to exclude cytotoxic effects. As presented in Fig 2, both geldanamycin and genistein seem to inhibit RET phosphorylation. For
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geldanamycin, however, we see that when the same blot is probed again with a RET antibody, the mature form of the receptor (170kD) decreases with the concentration of the inhibitor, suggesting an effect on the maturation of the RET protein instead of an inhibition of the catalytic activity of the receptor. In the right panel of Fig 2, we can compare it with the effect of genistein, a nonspecific tyrosine kinase inhibitor, which shows the results we expect. In conclusion, we think that RET is indeed a promising target for Gleevec inhibition. However, it is our view that the outcome of the study by Cohen and coworkers needs further analysis and experiments before it can be claimed that Gleevec is useful for the treatment of MTC through inhibition of RET activity. Ivan Plaza Menacho, MSc Jan Willem de Groot, MD Thera Links, MD, PhD John Plukker, MD, PhD Bart J.L. Eggen, PhD Robert Hofstra, PhD Departments of Medical Genetics and Developmental Genetics University Groningen Departments of Surgery and Internal Medicine Academical Hospital Groningen, The Netherlands
References
figures were of a quality high enough that other investigators are able to examine the data and reach their own conclusions. I would point out that in the body of the paper, we state that the percent inhibition of RET phosphorylation by the tyrosine kinase inhibitors (8% and 12%, respectively, at 5 and 20 umol/L concentrations of imatinib mesylate) was calculated using imaging software (NIH image version 1.6), and that values were adjusted for total RET protein loaded. Similar findings were reported by another group.1 We agree that further experiments could be done to evaluate the effectiveness of imatinib mesylate against medullary thyroid carcinoma. At present, however, there is no effective systemic therapy for patients with this lethal cancer. Clinical evaluation of these new agents is critical. The only way to determine if new agents are effective in patients is to perform clinical trials, and that is how we have proceeded. We are excited by the development of multiple new tyrosine kinase inhibitors, and MTC investigators are actively evaluating them. Dr Hofstra’s group has made seminal contributions to our understanding of the biology of this disease, and we look forward to their continued participation in this process. We thank the editors for providing us the opportunity to respond.
1. Cohen MS, Hussain HB, Moley JF. Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 2002;132:960-7.
Jeffrey F. Moley, MD Washington University School of Medicine Box 8109, 660 South Euclid Avenue St. Louis, MO 63110
doi:10.1016/j.surg.2003.11.005
Reply To the Editors: I would like to thank Dr Hofstra and his colleagues for their careful review of the data presented in ‘‘Inhibition of medullary thyroid carcinoma (MTC) cell proliferation and RET phosphorylation by tyrosine kinase inhibitors’’ (Surgery 2002;132:960-7). I am pleased that the published
References 1. Kikumori T, Hayashi H, Cote GJ, Scappini B, Beran M, Gagel RF. STI 571 [Gleevecä] inhibits growth of a human medullary thyroid carcinoma cell line with an activation RET proto-oncogene mutation. Proceedings of the Eighth International Workshop on Multiple Endocrine Neoplasia 2002; A52, Van Andel Institute, Grand Rapids, Michigan. doi:10.1016/j.surg.2003.11.006
Leo A. Gordon, MD, FACS Associate Director of Surgical Education Department of Surgery Cedars-Sinai Medical Center 8700 Beverly Blvd, Ste 8215 Los Angeles, CA 90048
240 SURGERY
References 1. Flexner A. Medical education in the United States and Canada—A report to the Carnegie Foundation for the Advancement of Teaching. New York: The Carnegie Foundation for the Advancement of Teaching; 1910. 50. doi:10.1016/j.surg.2003.11.003
Re: ‘‘Inhibition of medullary thyroid carcinoma (MTC) cell proliferation and RET phosphorylation by tyrosine kinase inhibitors’’ To the Editors: An important target for cancer research is the search for efficient anticancer drugs. Recently, tyrosine kinase inhibitors, in particular Gleevec, also known as Glivec, STI1571, and CGP57148B, have been used very successfully in the clinical management of chronic myelogenous leukemias and in gastrointestinal stromal tumors. The targets of Gleevec in these cancers are BCR-ABL and CKIT, both receptor tyrosine kinases. The success of Gleevec prompted many groups to investigate it in relation to other tumors expressing receptor tyrosine kinases similar to BCR-ABL or C-KIT. An obvious target is RET, a tyrosine kinase receptor often mutated in medullary thyroid carcinoma (MTC) and pheochromocytomas. In the December 2002 issue of this journal, Cohen, Hussain, and Moley described the use of Gleevec to inhibit RET activity in a cell line derived from an MTC.1 The authors reported that Gleevec inhibits both proliferation of this MTC cell line and RET tyrosine phosphorylation. The paper raises several questions that we would like to address in this letter. The first concerns the interpretation of Fig 1, which shows the effect of Gleevec on the tyrosine phosphorylation status of the RET receptor. The authors conclude from the upper panel of the figure that loss of tyrosine kinase activity correlates with an increase in the concentration of Gleevec. Indeed, the Western blot analysis shows a Gleevec concentration-dependent decrease in tyrosine-phosphorylated RET. However, when the same blot is probed again with a RET antibody, this amount also decreases with increasing concentrations of Gleevec. Therefore, a more correct conclusion would be that less RET is immunoprecipitated from cells treated with increasing Gleevec concentrations and, therefore, less tyrosine-phosphorylated RET is detected. Without a blot analysis of total cell lysates before immunoprecipitation, it is impossible to conclude how Gleevec treatment results in reduced RET protein levels. A second question concerns the fairly high concentration of Gleevec used for the cell proliferation studies. The data would be more convincing if the authors had tested these concentrations on several control cell lines to exclude cytotoxic effects. As presented in Fig 2, both geldanamycin and genistein seem to inhibit RET phosphorylation. For
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Surgery Volume 135, Number 2
geldanamycin, however, we see that when the same blot is probed again with a RET antibody, the mature form of the receptor (170kD) decreases with the concentration of the inhibitor, suggesting an effect on the maturation of the RET protein instead of an inhibition of the catalytic activity of the receptor. In the right panel of Fig 2, we can compare it with the effect of genistein, a nonspecific tyrosine kinase inhibitor, which shows the results we expect. In conclusion, we think that RET is indeed a promising target for Gleevec inhibition. However, it is our view that the outcome of the study by Cohen and coworkers needs further analysis and experiments before it can be claimed that Gleevec is useful for the treatment of MTC through inhibition of RET activity. Ivan Plaza Menacho, MSc Jan Willem de Groot, MD Thera Links, MD, PhD John Plukker, MD, PhD Bart J.L. Eggen, PhD Robert Hofstra, PhD Departments of Medical Genetics and Developmental Genetics University Groningen Departments of Surgery and Internal Medicine Academical Hospital Groningen, The Netherlands
References
figures were of a quality high enough that other investigators are able to examine the data and reach their own conclusions. I would point out that in the body of the paper, we state that the percent inhibition of RET phosphorylation by the tyrosine kinase inhibitors (8% and 12%, respectively, at 5 and 20 umol/L concentrations of imatinib mesylate) was calculated using imaging software (NIH image version 1.6), and that values were adjusted for total RET protein loaded. Similar findings were reported by another group.1 We agree that further experiments could be done to evaluate the effectiveness of imatinib mesylate against medullary thyroid carcinoma. At present, however, there is no effective systemic therapy for patients with this lethal cancer. Clinical evaluation of these new agents is critical. The only way to determine if new agents are effective in patients is to perform clinical trials, and that is how we have proceeded. We are excited by the development of multiple new tyrosine kinase inhibitors, and MTC investigators are actively evaluating them. Dr Hofstra’s group has made seminal contributions to our understanding of the biology of this disease, and we look forward to their continued participation in this process. We thank the editors for providing us the opportunity to respond.
1. Cohen MS, Hussain HB, Moley JF. Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 2002;132:960-7.
Jeffrey F. Moley, MD Washington University School of Medicine Box 8109, 660 South Euclid Avenue St. Louis, MO 63110
doi:10.1016/j.surg.2003.11.005
Reply To the Editors: I would like to thank Dr Hofstra and his colleagues for their careful review of the data presented in ‘‘Inhibition of medullary thyroid carcinoma (MTC) cell proliferation and RET phosphorylation by tyrosine kinase inhibitors’’ (Surgery 2002;132:960-7). I am pleased that the published
References 1. Kikumori T, Hayashi H, Cote GJ, Scappini B, Beran M, Gagel RF. STI 571 [Gleevecä] inhibits growth of a human medullary thyroid carcinoma cell line with an activation RET proto-oncogene mutation. Proceedings of the Eighth International Workshop on Multiple Endocrine Neoplasia 2002; A52, Van Andel Institute, Grand Rapids, Michigan. doi:10.1016/j.surg.2003.11.006