Quemener V, Chamaillard L, Brachet P, Havouis R, Moulinoux J P
Laboratoire de Biologie Cellulaire, GRETAC, URA CNRS 1529, CHU de Rennes.
Bull Acad Natl Med. 1994 Nov;178(8):1591-605; discussion 1606-8.
The fact that tumors require polyamines for growth has been repeatedly demonstrated. In vivo polyamines are available both from endogenous (intracellular biosynthesis) and exogenous sources (food and intestinal microflora). We investigated in rats grafted with Mat-Lylu prostatic adenocarcinoma the distribution between tumor and tissues of orally administered [14C]putrescine (Pt). The amount of radioactivity retained by tumors was directly proportional to the tumor volume. In a tumor of 25 cm3 19% of the totally retained radioactivity was found. The accumulation of Pt by intestinal brush-border membrane vesicles prepared from tumor-bearing animals was significantly higher than by vesicles from healthy rats. Our results indicate that the presence of a tumor induces an adaptive response in the small intestine which stimulates the uptake of exogenous polyamines. Our therapeutic strategy was to realise a total blockade of all endogenous and exogenous sources of polyamines by feeding animals with a drug (DFMO, MDL 72527, antibiotics) containing polyamine deficient chow. We observed that polyamine deprivation largely reduced both primary tumor and metastatic development. Natural Killer cell cytotoxic activity and blood formula were restored to normal values after treatment. Furthermore polyamine deprivation enhanced antitumoral efficacy of chemotherapy.
肿瘤生长需要多胺这一事实已得到反复证实。在体内，多胺可来自内源性（细胞内生物合成）和外源性来源（食物和肠道微生物群）。我们在接种了Mat-Lylu前列腺腺癌的大鼠中研究了口服[14C]腐胺（Pt）在肿瘤和组织之间的分布情况。肿瘤保留的放射性量与肿瘤体积直接成正比。在一个25立方厘米的肿瘤中，发现其保留了总放射性的19%。从荷瘤动物制备的肠刷状缘膜囊泡对Pt的积累明显高于健康大鼠的囊泡。我们的结果表明，肿瘤的存在会在小肠中诱导一种适应性反应，刺激对外源性多胺的摄取。我们的治疗策略是通过给动物喂食含有多胺缺乏饲料的药物（二氟甲基鸟氨酸、MDL 72527、抗生素）来实现对内源性和外源性多胺来源的完全阻断。我们观察到，多胺剥夺在很大程度上减少了原发性肿瘤和转移的发展。治疗后自然杀伤细胞的细胞毒性活性和血常规恢复到正常水平。此外，多胺剥夺增强了化疗的抗肿瘤疗效。
