【交流】胰岛素会引起癌症吗——关于来得时

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从网上看到的国外一篇文章，很有趣。附英语原文

最近有研究发现，长期使用长效胰岛素类似物来得时有可能会带来一个很严重的问题——癌症。
来得时在2000年被美国食品药品管理局（FDA）批准在美国上市，但是在获得欧洲药审委（EMEA）批准欧洲上市之前，被发现在体外试验中具有很高的促人骨肉瘤细胞（一种恶性肿瘤细胞）增殖的作用。来得时的生产商赛诺菲－安万特公司向欧洲药审委口头陈述了这个信息，而药审委认为这与来得时无关，所以批准其在欧洲上市。

质疑一
2000年6月的《糖尿病》上就曾刊登过来得时的促骨肉瘤细胞增殖作用的研究。此研究发现，来得时促进细胞增殖的作用是人胰岛素的6－8倍，这种作用是通过**IGF－1（**－1）受体来产生的。而其他研究则发现IGF－1与癌症之间存在相关性：在1999年4月的美国《国家癌症研究所杂志》上发表的一项研究显示血中的IGF－1水平与结肠直肠癌的发病风险有关。在1998年5月的《柳叶刀》上发表的另一项研究发现，血中IGF－1浓度与绝经前妇女乳腺癌风险呈正相关（即浓度越高，风险越大），而在绝经后妇女中没有发现这种关系。
因此，有人提出：既然已经发现IGF－1水平升高至少会增加两种癌症的风险，而现在又发现来得时具有类IGF－1的作用，这说明来得时可能会增加癌症风险。但是，它所潜在的增加癌症发生率的作用究竟有多大，目前还不清楚。
的确，来得时引起的IGF－1受体表达的增加与一些类型的癌症发病有关，但是这一结果只是来自于体外试验，在人体内还未得到证实。目前，还没有切实的证据显示使用来得时会增加癌症风险。

质疑二
在2002年6月的《毒物学》上又刊登了一项关于来得时潜在的致癌作用的研究，但是研究中所使用的来得时剂量要远远低于另一种胰岛素类似物B10Asp当年的试验剂量。（注：B10Asp由于在老鼠试验中发现具有促乳腺癌作用，其临床试验在1992年就被中止了，所以也就没能上市。）简而言之，这就意味着来得时可能具有和B10Asp相似的致癌作用。
赛诺菲－安万特公司的研究人员指出，他们就来得时的致癌作用在小鼠和大鼠中都进行了研究，但均未显示出致癌效应。
不过，赛诺菲－安万特公司的发言人并未否认Asp- B10在啮齿类动物试验中被发现具有促**肿瘤细胞生长的作用。他讲到，“来得时有可能是由于具有某种特殊的促生长作用，所以才表现出促进肿瘤细胞增殖的作用。我们用Asp-B10作为来得时临床前试验的对比物，发现Asp-B10具有与人胰岛素和来得时所不同的受体激活作用。广泛的研究清楚地证实了来得时并不存在安全性问题，这些研究包括临床前体外试验和动物毒理试验。”这位发言人还补充说，来得时是唯一一个进行了两年的动物毒理研究的胰岛素类似物，而在为期两年的啮齿类动物研究中未发现任何的致癌证据。

观点之争
赛诺菲－安万特公司的发言人指出，来得时的使用者们不应该过于看重来得时致癌的这种理论，因为用于那些研究的老鼠本身就很容易发生某些类型的癌症。他解释说胰岛素可以和IGF－1受体结合，也可以和胰岛素受体结合；但是如果同时存在胰岛素受体和IGF－1受体，胰岛素将会和胰岛素受体相结合而不与IGF－1受体结合。用于研究的老鼠是经过特别培育的不具有胰岛素受体的特殊种类，所以胰岛素（或来得时）唯一可以与之结合的就只有IGF－1受体了，而这样就必然会**肿瘤的形成。但事实上人类体内都存在胰岛素受体，所以这种担忧是没有必要的。
但有的研究者并不同意这种观点，其理由是只要存在有效的IGF－1受体，即便有胰岛素受体存在，还是会有一部分胰岛素与IGF－1受体结合的。按照“质量作用定律”，即使大多数胰岛素都会和胰岛素受体结合，但仍然还会有很少一部分胰岛素与IGF－1受体结合的。所以，并不能一定就说来得时在人体内不会致癌。
赛诺菲－安万特公司则认为，经过对2000多位患者长达52周的临床研究已经证实来得时不仅高效而且具有很好的耐受性。公司所收集的广泛的临床前数据和上市后的临床数据都没有显示使用来得时存在致癌风险。此外，公司还准备对超过1万5千位患者进行进一步的药物不良作用监控。
自来得时投放市场以来，其临床安全性评价结果都写在了说明书上，并一直通过定期安全性更新报告（Periodic Safety Update Report，简称PSUR）不断进行更新。更多内容可以阅读说明书上“致癌作用、致突变作用、生殖毒性”的部分。
专家指出：来得时是否具有致癌作用可能需要通过对使用来得时的人群进行长期研究才能确定。目前的这些数据只能提示我们理论上存在这种可能性，但是仅此而已，其确切情况我们还不知道，所以还需要等待更进一步的研究结果。
Can Insulin Cause Cancer?
Potentially serious problem

Tags: Feature Articles, Insulin, Type 1, Type 2
Daniel Trecroci
February 2006
Richard K. Bernstein, MD, says that a potentially serious problem with eliminating Ultralente is the “long-term forecast of potential aderse effects” in people taking Lantus, as outlined by Ernst Chantelau, MD.
Chantelau is a professor in the department of endocrinology, diabetes and rheumatology at Diabetesambulanz MNR-Klinik in Dusseldorf, Germany. In a paper Chantelau co-authored with Jenny Hirst for the Insulin Dependent Diabetes Trust, he speculates that cancer may be a long-term side effect of taking Lantus.
Lantus was approed by the U.S. Food and Drug Administration in 2000. Chantelau says that before the European Medicines Ealuation Agency (EMEA) was asked to approe Lantus in Europe, “it was found to be highly mitogenic [causing cell proliferation] on in itro testing with human osteosarcoma cells [cancerous cells from tissue surrounding bone].” Chantelau says that Aentis presented this ***rmation to the EMEA orally, and the EMEA decided it was “irreleant.” Lantus was then approed.
Chantelau claims, howeer, that that “the mitogenicity of Lantus on osteosarcoma cells” was publicly disclosed in the June 2000 issue of the journal Diabetes. According to that study, which was conducted by Peter Kurtzhals, senior ice president of diabetes research for Noo Nordisk A/S, human cancer cells (not animal cells) in culture were studied to measure to what extent Lantus stimulated cell growth. Kurtzhals found that, “The combination of the B31B32diArg and A21Gly substitutions proided [Lantus] with a six- to eight-fold increased IGF-1 receptor affinity and mitogenic potency compared with human insulin.”
According to Bernstein’s translation of Kurthzhal’s finding, this means Lantus is much more likely to stimulate IGF-1 receptors than is human insulin. This is important, Bernstein argues, because other studies hae drawn connections between IGF-1 and cancer. For instance, in the April 7, 1999, issue of the Journal of the National Cancer Institute, Harard researchers found that circulating IGF-1 is related to future risk of colorectal cancer.
According to another study published in the May 1998 issue of the Lancet, Harard researchers found a positie relation between circulating IGF-1 concentration and risk of breast cancer among premenopausal but not postmenopausal women.
“We know of at least two cancers that are accelerated by IGF-1,” says Bernstein. “IGF-1 is associated with cancer, and now we find out that Lantus behaes like IGF-1. So what are we to conclude? I’m certainly concerned, but I hae no idea of the magnitude of potential risk, if any.”
Kurtzhals admitted to Diabetes Health that “increased IGF-1 receptor expression has been associated with some forms of cancer.” When asked if the data from his study is an indicator that Lantus may cause cancer in humans, howeer, Kurtzhals said, “These findings were made in cell lines, and there is no experience to project these findings to risk in humans…There is no eidence for an increased cancer risk in people taking Lantus.”
Taking the argument one step further, Chantelau also claims that when Lantus was later studied for its carcinogenic potential in another study (reported in the June 2002 issue of the International Journal of Toxicology), dosages were used that were much lower than those of the ill-fated insulin **ogue B10Asp. B10Asp was an **ogue insulin that neer made it to market after clinical trials were stopped in 1992 when it was shown to promote breast cancer in rats.
“In short, this means that Lantus may hae a similar carcinogenic potential as…B10Asp,” says Chantelau.
Ingo Stammberger of Aentis Pharma Germany in Hattersheim, Germany, was a lead researcher on the International Journal of Toxicology study. He told Diabetes Health that Lantus was studied in rat and mouse carcinogenicity studies and that in both studies, it “did not show a carcinogenic effect.”
Sanofi-Aentis spokespersons do not refute that Asp- B10 had been found to promote growth of mammary tumors in rodent toxicology studies.
“In the case of Lantus, the question was raised as to whether insulin **ogues and Lantus may hae specific growth promoting potential, which could be expressed as tumor-promoting actiity in patients,” say Sanofi-Aentis spokespersons. “Asp-B10 was used as a comparator in the preclinical studies with Lantus and found to hae a profile of receptor actiation that is different from human insulin and from Lantus. Extensie inestigation with Lantus has clearly established that there is no safety risk with the use of Lantus. This eidence includes preclinical in itro studies on receptors and cell lines as well as toxicology studies in animals.”
Sanofi-Aentis adds that Lantus is the only insulin **ogue that has been inestigated in two-year animal toxicology studies.
“The two-year rodent carcinogenicity studies show no eidence of carcinogenicity.”
Nancy Bohannon says Lantus users should not look too deeply into Chantelau’s theories, because she claims the rats used in the studies were “ery prone to certain types of cancer.” Bohannon adds that the researchers were using specially bred rats that didn’t hae insulin receptors.
“Insulin binds to insulin like growth factor [IGF-1] receptors, and it binds to insulin receptors,” says Bohannon. “But if you hae insulin receptors and IGF-1 receptors, it will bind to the insulin receptors and not the IFG-1 receptors. This was a specially bred strain that did not hae insulin receptors, so the only thing to bind to was the IGF-1 receptors. And when you bind to the IGF-1 receptors, that can stimulate the formation of tumors. ” Bohannon says that you are neer going to hae humans who don’t hae any insulin receptors, so she calls Chantelau’s claims “far reaching.”
Richard Bernstein, howeer, disagrees with Bohannon’s assessment.
“There is a law of physics that when you get down to molecular through subatomic dimensions, if it can happen, it will happen,” says Bernstein. “If you hae IGF-1 receptors aailable, een though you hae insulin receptors, insulin is going to bind to some of them. In chemistry, it is called the ‘law of mass action.’ Most of it will go to the insulin receptors, but a little of it will hit the IGF-1 receptors. So we probably should not use that as an argument that it can’t cause cancer.”
Stuart Brink says that in order to answer any questions about cancer risk, long-term studies in humans who hae taken Lantus would need to be done.
“The current data do not suggest this is anything but a theoretical issue,” says Brink. “We just don’t know.”
Bernstein also agrees that “we just don’t know.”
Chantelau admits that the data gathered from rat studies do not tell us anything about the potential risk of cancer promotion.
“As we still don’t know whether insulin **ogues are cancer-promoting or not, I and others hae been asking for the inestigation of insulin **ogues on cancer tissues,” says Chantelau. “These studies are still lacking.”
Sanofi-Aentis disagrees, pointing out that Lantus has been “highly effectie and well tolerated” throughout a comprehensie clinical trial program inoling more than 2,000 patients treated with Lantus for up to 52 weeks, as well as clinical use since 2000 by more than one million patients with diabetes.
“The extensie preclinical safety data and clinical post-marketing data collected by Sanofi-Aentis indicate there is no carcinogenic safety risk with the use of Lantus.”
In addition, Sanofi-Aentis says mechanisms are in place to report any increase in cancer in patients.
“…We monitor possible aderse effects in our ongoing comparatie trials of more than 15,000 patients.”
The results of the clinical safety ealuations are included in the prescribing ***rmation for Lantus. Since its market launch, this ***rmation has been continually updated by post-marketing sureillance under study and practice conditions and by Periodic Safety Update Reports.
For more ***rmation, see the section labeled “Carcinogenesis, Mutagenesis, Impairment of Fertility” on the prescribing label of your Lantus bottle.

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最近看了一些其他资料 好象否定了这一结论 这质疑在6年前就有人提出来的