SELECTIVE KILLING OF HUMAN-MALIGNANT CELL-LINES DEFICIENT IN METHYLTHIOADENOSINE PHOSPHORYLASE, A PURINE METABOLIC ENZYME
SELECTIVE KILLING OF HUMAN-MALIGNANT CELL-LINES DEFICIENT IN METHYLTHIOADENOSINE PHOSPHORYLASE, A PURINE METABOLIC ENZYME
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DOI：
10.1073/pnas.78.2.1219
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发表时间：
1981-01-01
期刊：
影响因子：
--
通讯作者：
CARSON, DA
中科院分区：
文献类型：
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作者：
KAMATANI, N;NELSONREES, WA;CARSON, DA
用5“-氯腺苷作为底物测定，31个人恶性肿瘤细胞系中的7个（23%）没有可检测到的甲硫腺苷磷酸化酶活性（< 0.001 nmol/min/mg蛋白质）。酶缺陷细胞系来自5例白血病、1例黑色素瘤和1例乳腺癌。来自淋巴细胞、成纤维细胞和上皮细胞的16种非恶性来源的细胞系均不缺乏该酶（范围为0.156-1.447 nmol/min/mg蛋白质）。通过放射自显影检测，完整的酶阳性细胞系、正常的未成熟骨髓细胞和4个恶性肿瘤细胞标本将5“-氯腺苷的腺嘌呤部分掺入核酸中;然而，没有酶缺陷细胞系使用5”-氯腺苷。当两种类型的细胞系在含有0.4 μ M甲氨蝶呤、16 μ M尿苷和16 μ M胸苷（或单独10 μ M阿扎胞苷）的培养基中培养时，没有细胞生长。如果将甲硫腺苷加入到相同的培养基中，只有酶阳性细胞的数量增加;大多数酶缺陷细胞在3天后死亡。因此，当从头嘌呤合成被抑制并且甲硫基腺苷是嘌呤的唯一外源性来源时，可以选择性地杀死甲硫基腺苷磷酸化酶天然缺陷的人恶性肿瘤细胞系。[讨论了可能的化疗应用。]
Seven of 31 (23%) human malignant tumor cell lines had no detectable methylthioadenosine phosphorylase activity (< 0.001 nmol/min per mg of protein), assayed with 5''-chloroadenosine as substrate. The enzyme-deficient cell lines were derived from 5 leukemias, 1 melanoma and 1 breast cancer. None of 16 cell lines of nonmalignant origin, derived from lymphocytes, fibroblasts and epithelial cells, lacked the enzyme (range, 0.156-1.447 nmol/min per mg of protein). As detected by autoradiography, intact enzyme-positive cell lines, normal immature bone marrow cells, and 4 specimens of malignant tumor cells incorporated the adenine moiety of 5''-chloroadenosine into nucleic acids; however, no enzyme-deficient cell lines used 5''-chloroadenosine. When both types of cell lines were cultured in a medium containing 0.4 .mu.M methotrexate, 16 .mu.M uridine, and 16 .mu.M thymidine (or 10 .mu.M azaserine alone), no cells grew. If methylthioadenosine was added to the same medium, only enzyme-positive cells increased in number; most enzyme-deficient cells were dead after 3 days. Thus, human malignant tumor cell lines naturally deficient in methylthioadenosine phosphorylase could be selectively killed when de novo purine synthesis was inhibited and methylthioadenosine was the only exogenous source of purines. [Possible chemotherapeutic applications were discussed.].