de Castiglione R, Gozzini L, Galantino M, Corradi F, Arlandini E, Molinari I, Ciomei M
Farmitalia Carlo Erba S.r.l.-Erbamont Group, Milano, Italy.
Farmaco. 1991 Jun;46(6):743-57.
Bombesin (BN)-like peptides (such as GRP, gastrin-releasing peptide) are autocrine growth factors for small cell lung carcinoma (SCLC). BN receptor antagonists can therefore find clinical application in the treatment of this highly malignant disease. The present paper deals with a new class of bombesin analogues carrying a nitrogen mustard at their N-terminus. Due to the irreversible binding to the BN receptor(s), these peptides eventually block the mitogenic effects of the natural ligand(s), regardless of their intrinsic "agonistic" or "antagonistic" structures. In Swiss 3T3 fibroblasts they inhibit [125I]GRP binding in the nanomolar/micromolar range. According to their "agonistic" or "antagonistic" structural features, they do or do not induce [3H]thymidine incorporation and p 115 phosphorylation. In competition experiments, alkylating "antagonists" selectively inhibit BN-induced thymidine incorporation either when given simultaneously with or 24 hours before the BN challenge. Alkylating "agonists" display antagonistic effects only in the sequential treatment.
蛙皮素（BN）样肽（如胃泌素释放肽，GRP）是小细胞肺癌（SCLC）的自分泌生长因子。因此，BN受体拮抗剂可在这种高恶性疾病的治疗中找到临床应用。本文研究了一类新型的在其N端带有氮芥的蛙皮素类似物。由于它们与BN受体的不可逆结合，这些肽最终会阻断天然配体的促有丝分裂作用，无论其内在的“激动剂”或“拮抗剂”结构如何。在瑞士3T3成纤维细胞中，它们在纳摩尔/微摩尔范围内抑制[125I]GRP结合。根据其“激动剂”或“拮抗剂”的结构特征，它们会或不会诱导[3H]胸苷掺入和p115磷酸化。在竞争实验中，烷基化“拮抗剂”在与BN同时给药或在BN刺激前24小时给药时，均能选择性抑制BN诱导的胸苷掺入。烷基化“激动剂”仅在序贯治疗中显示拮抗作用。
