Retsky Michael W, Hrushesky William J M, Gukas Isaac D
Department of Vascular Biology, Children's Hospital and Harvard Medical School, Boston 02115, MA, USA.
BMC Cancer. 2009 Jan 8;9:7. doi: 10.1186/1471-2407-9-7.
Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing.
The therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems.
We propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that develops, as happens in most cancer therapies.
患有唐氏综合征的女性极少患乳腺癌，尽管她们如今活到了乳腺癌通常发病的年龄。这可能与唐氏综合征患者的21号染色体多了一个副本有关，而编码抗血管生成蛋白内皮抑素的基因就位于该染色体上。这一信息能否促成针对早期乳腺癌的原发性抗血管生成疗法，从而无限期延长缓解期呢？由此产生的一个关键问题是，微转移灶中最初的血管生成开关何时开启？我们推测，无血管微转移灶处于休眠状态，若不受干扰则相对稳定，但对一些患者而言，手术会促使血管生成。我们还提出，在手术切除原发性肿瘤之前，微转移灶极少发生血管生成。倘若如此，似乎我们可以提出一种原发性抗血管生成疗法，但随之而来的问题是，在手术前开始治疗会干扰伤口愈合。
该疗法必须在手术切除原发性肿瘤至少一天前开始，并可能无限期维持在唐氏综合征患者的水平。这意味着该药物必须几乎没有毒性，且不会对伤口愈合产生明显干扰。这特别排除了那些显著抑制VEGF通路的药物，因为这对伤口愈合很重要，而且这些药物有一定毒性。内皮抑素显然无毒，且不会对伤口愈合产生明显干扰，因为唐氏综合征患者没有异常的伤口愈合问题。
我们提出一种针对早期乳腺癌的疗法，即从手术前至少一天开始，使用处于或高于唐氏综合征患者水平的内皮抑素，并持续维持该水平。这应能预防手术或之后任何时候导致的微转移灶血管生成。辅助化疗或激素疗法应该不再必要。这种疗法可以无限期持续，因为不会像大多数癌症疗法那样产生获得性耐药。
