Guo H, Tan Y, Kubota T, Moossa A R, Hoffman R M
AntiCancer, Inc., San Diego, CA 92111, USA.
Anticancer Res. 1996 Sep-Oct;16(5A):2719-23.
The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.
肿瘤生长对蛋氨酸的需求增加，即所谓的蛋氨酸依赖性，是一个潜在的高效治疗靶点。为了攻克这一靶点，我们正在研发抗蛋氨酸化疗方法。在这项抗蛋氨酸化疗研究中，我们观察到蛋氨酸类似物乙硫氨酸在体外以及移植到裸鼠体内时，与蛋氨酸耗竭协同作用，可抑制吉田肉瘤的生长。相比之下，在含蛋氨酸的培养基中，乙硫氨酸对吉田肉瘤细胞无效。同样，与含蛋氨酸的饮食一起给予乙硫氨酸，对裸鼠体内生长的吉田肉瘤也无效。仅采用蛋氨酸耗竭饮食对肿瘤生长仅有部分效果。在喂食含蛋氨酸饮食的小鼠中，观察到75%的器官出现吉田肉瘤转移，而在无蛋氨酸饮食的小鼠中，这一比例为43%。与之形成鲜明对比的是，在无蛋氨酸饮食的乙硫氨酸处理动物中未观察到转移现象。由饮食中蛋氨酸耗竭和给予乙硫氨酸组成的抗蛋氨酸化疗最初导致动物体重减轻，但随后体重稳定，无动物死亡。乙硫氨酸与蛋氨酸耗竭的协同作用在体外和体内显著相似，这表明所观察到的疗效归因于特定的抗蛋氨酸靶向作用。因此，蛋氨酸耗竭极大地增强了乙硫氨酸的抗肿瘤和抗转移效果，这表明由蛋氨酸耗竭作为蛋氨酸类似物调节剂组成的抗蛋氨酸化疗作为一种新的肿瘤选择性治疗方法具有很大的前景。
