位于Hershey的宾夕法尼亚州立大学医学院的研究人员利用组织培养和裸鼠移植肿瘤实验发现低剂量的阿片拮抗剂纳曲酮（LDN）对人卵巢癌有非常有效的抗肿瘤作用。当LDN与化疗药物一起使用时，更有加成性的肿瘤抑制作用。这一个发表在2011年7月发行的 《实验生物及医学》期刊的新发现，提供了卵巢肿瘤新的病理机制和治疗方法。卵巢肿瘤是美国妇女第四大癌症死亡的原因。
利用LDN抑制癌症的策略首先于30年前由Zagon和McLaughlin两位博士提出（《科学 》杂志第221期;671-673页）。纳曲酮（NTX）是一个阿片受体的拮抗剂，因为他缺乏内在的活性，所以会导致细胞内的阿片类分子和阿片受体补偿性的增加。短时间（每天四到六小时）利用LDN 阻断阿片和受体间的作用，可提供足够的时间（8-20小时）让细胞内升高的阿片和其受体结合，并进而产生抑制细胞增生的效用。因此，LDN可作为一个上调自身阿片类分子和阿片受体的诱饵。当外加的纳曲酮被代谢而消失以后，阿片分子及受体结合的作用反而会增强。内源性阿片肽，阿片生长因子（OGF）（化学术语= [Met5]脑啡肽）以及受体（OGFr）和LDN共同作用，构成间歇性主动抑制轴线，透过细胞周期蛋白依赖性激酶抑制路径抑制DNA的合成而抑制细胞的增生。该实验室先前已发现人类卵巢癌细胞内OGF- OGFr轴是存在而且有功能的（美国生理学期刊第296期：R1716-1725，2009年）。
本研究探讨的问题着眼于利用LDN来调控体内的OGF-OGFr轴是否可以改变卵巢肿瘤的进展。此外，作者也想了解是否可以结合LDN与标准化疗而对卵巢癌产生更好的治疗效果。组织培养实验发现，将人类卵巢癌细胞每隔两天暴露于NTX 6小时，会降低DNA合成和细胞复制。当将卵巢癌细胞短时间处理LDN后再施予标准化疗药物，紫衫醇或顺箔时，发现疗效比用单独化学治疗药物时更好。 LDN的效果是可逆的，显示他并没有毒性反应。虽然在组织培养情况下，LDN不论是单独使用或是和化疗药物一起作用，效果都相当好。但在肿瘤移植的老鼠身上是否有一样的效果，则有待验证。因此作者更进一步利用肿瘤移植于裸鼠的实验来验证。结果发现LDN可以抑制肿瘤的增生，降低去氧核糖核酸合成以及血管新生，但不改变细胞的存活率。 LDN抑制肿瘤增生的效果和顺箔或是紫衫醇的效果相当。然而当LDN 和顺箔一起作用时，其效果远胜于单独使用LDN或是紫衫醇。此外，顺箔对于裸鼠是有毒性的，会造成体重下降。然而当LDN和顺箔一起作用时，可以减少顺箔的毒性，显示LDN对于化疗药物所产生的不良副作用有缓解的效果。 LDN被发现可以增加OGF和OGFr的表现量，显示这个内生性的、抑制细胞增生的阿片系统可以被LDN活化。
这个研究团队是由神经与行为科学系的Ian Zagon特聘教授、McLaughlin教授以及博士班学生Renee Donahue所组成。 Zagon博士和McLaughlin博士在探讨LDN以及OGF的基础和临床特性上已经有长久的合作经验。第一期和第二期的临床研究发现LDN在治疗Crohn氏症是有效的而且OGF也被发现在治疗胰岛腺癌上是安全而且有效的。本文共同作者McLaughlin说：「基于OGF-OGFr独特的细胞增生调控作用以及LDN可以增加阿片与阿片受体的生物作用之机制，这是一个相当吸引人的利用生物方式抑制卵巢癌增生的疗法」。Zagon博士进一步引伸说：「由于缺乏诊断标志物，超过75％的女性患者只有在晚期的卵巢癌才被诊断出来。虽然细胞减灭术及术后化疗在最初的临床反应不错，但有将近65％的后期的卵巢癌病人在2年内复发。所有后续治疗都是消极的减缓病痛而已。因此，我们研究的临床意义在于说明在临床试验中使用LDN治疗晚期卵巢癌的紧迫性」。
《实验生物及医学》期刊的主编Steve Goodman博士说：“宾夕法尼亚州立大学医学院的研究人员发现，低剂量的阿片拮抗剂纳曲酮显著抑制移植到小鼠体内的人类卵巢癌之进展。低剂量的纳曲酮结合顺铂的治疗方式，有更好的肿瘤抑制作用。因此，低剂量纳曲酮提供了一种无毒的和有效的生物途径疗法，可能对卵巢癌患者有所助益”。
生物探索推荐英文原文
Low dose naltrexone (LDN): Harnessing the body's own chemistry to treat human ovarian cancer
Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered that a low dose of the opioid antagonist naltrexone (LDN) has an extraordinarily potent antitumor effect on human ovarian cancer in tissue culture and xenografts established in nude mice. When LDN is combined with chemotherapy, there is an additive inhibitory action on tumorigenesis. This discovery, reported in the July 2011 issue of Experimental Biology and Medicine, provides new insights into the pathogenesis and treatment of ovarian neoplasia, the 4th leading cause of cancer-related mortality among women in the United States.
The strategy of LDN therapy in repressing cancer was first reported over 30 years ago by Drs. Zagon and McLaughlin (Science 221:671-673). Naltrexone (NTX) is a general opioid receptor antagonist devoid of intrinsic activity that results in a compensatory elevation in endogenous opioids and opioid receptors. Blockade of opioid peptides from opioid receptors for a short time each day (4 to 6 hr) with LDN provides a sufficient window of time (18-20 hr) for the elevated levels of endogenous opioids and opioid receptors to interact and elicit a response: inhibition of cell proliferation. Thus, LDN acts as a decoy to upregulate native opioids and opioid receptors. When NTX is metabolized and no longer present, an enhanced opioid-receptor effect is permitted to occur. The endogenous opioid peptide, opioid growth factor (OGF) (chemical term = [Met5]-enkephalin) and its receptor (OGFr) is related to LDN action, and constitutes a tonically active inhibitory axis that suppresses cell proliferation through a depression in DNA synthesis by way of cyclin-dependent kinase inhibitory pathways. In the case of human ovarian cancer, this laboratory (Amer. J. Physiol. 296:R1716-1725, 2009) previously found that the OGF-OGFr axis is present and functional in human ovarian cancer.
The present study addressed the question of whether modulation of the OGF-OGFr axis by LDN could alter the progression of established ovarian tumors. Moreover, the authors asked whether LDN can be combined with standard chemotherapy to invoke an even greater effect on ovarian cancer. A model of LDN in tissue culture was established that exposed human ovarian cancer cells to NTX for 6 hr every two days, resulting in reduced DNA synthesis and cell replication from vehicle subjected controls. When a short term exposure to NTX was combined with standard of care chemotherapeutic agents, taxol or cisplatin, an enhanced anticancer action relative to either drug was observed. The effects of LDN, but not taxol or cisplatin, could be reversed, indicating the non-toxic nature of LDN. Although favorable results with LDN alone and in combination with chemotherapeutic drugs were recorded in a tissue culture setting, this begged the question of whether LDN was effective on tumors transplanted into mice. Using nude mice with established xenografts of human ovarian cancer, LDN was found to repress tumor progression, reducing DNA synthesis and angiogenesis but not altering cell survival. LDN's repression of cancer progression was comparable to that of cisplatin or taxol. However, the combination of LDN with cisplatin, but not taxol, had an even greater antitumor effect than LDN or taxol alone. Moreover, cisplatin was toxic to the mice, as detected by weight loss. However, LDN in combination with cisplatin attenuated the toxicity of this chemotherapeutic agent, indicating that LDN was protective of the adverse events elicited by a chemotherapeutic drug. Finally, LDN was discovered to upregulate the expression of both OGF and OGFr, indicating that this endogenous opioid system, which inhibits cell proliferation, was activated by LDN.
The research team was comprised of Dr. Ian S. Zagon, Distinguished University Professor, and Dr. Patricia J. McLaughlin, Professor, along with a doctoral student, Dr. Renee N. Donahue, in the Department of Neural & Behavioral Sciences. Drs. Zagon and McLaughlin have extensive collaborations focused on demonstrating the remarkable properties of LDN and OGF in a variety of preclinical and clinical studies. LDN has proven successful in Phase I and II clinical trials in the treatment of Crohn's disease, and OGF has been found to be safe and efficacious for pancreatic cancer. Co-author Dr. McLaughlin states: "Given the extraordinary biological control of the OGF-OGFr axis with respect to cell proliferation, and the unique modulatory capability of LDN to enhance opioid-receptor response by way of native biological processes, this is particularly attractive as a biological-based treatment in arresting the progression of ovarian cancer." Dr. Zagon adds that "More than 75% of women are diagnosed with ovarian cancer in advanced stages because of a lack of diagnostic biomarkers. Although the initial clinical response to cytoreductive surgery and adjuvant chemotherapy is excellent, nearly 65% of advanced-staged patients relapse within 2 years. All subsequent treatments are pallative. Thus, the clinical implications of our study speak to the urgency for initiating clinical trials using LDN in the treatment of advanced ovarian cancer."
Steven Goodman, Ph.D. Editor-in-Chief of Experimental Biology and Medicine said “Researchers at The Pennsylvania State University College of Medicine have discovered that a low dose of the opioid antagonist naltrexone markedly suppresses progression of human ovarian cancer transplanted into mice. Low dose naltrexone combined with cisplatin, but not taxol, had an additive inhibitory action on tumorigenesis. Therefore low dose naltrexone offers a non-toxic and efficacious biologic pathway-related treatment that may benefit patients with this ovarian cancer.”
