Everard M J, Macaulay V M, Miller J L, Smith I E
Section of Medicine, Royal Marsden Hospital, Belmont, Surrey, UK.
Br J Cancer. 1992 Mar;65(3):388-92. doi: 10.1038/bjc.1992.78.
Analogues of the neurotransmitter substance P (SP) can interact with neuropeptide receptors, and are reported to inhibit growth of small cell lung cancer cell lines (SCLC CLs). We found [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P (D-Phe5SP) significantly inhibited DNA synthesis by 10/10 human tumour CLs; six SCLC, one N-SCLC (squamous), two ovarian and one squamous cervical carcinoma, with inhibition to 50% control levels (IC50) of 20-50 microM. There was dose dependent inhibition of colony forming efficiency (CFE) in 3/3 SCLC and 1/1 N-SCLC CL, IC50s of 0.5-6.5 microM in 5% serum. Exposure of SCLC CL HC12 to 100 microM D-Phe5SP for 1-4 h caused a progressive fall in viable cell number; surviving cells, grown in the absence of peptide, showed a decreased growth rate. During 1 week's exposure of two SCLC CLs to 20 microM D-Ph5SP, growth was slower than control cultures, while 50-100 microM completely inhibited growth. These inhibitory effects were partially reversed by increasing serum concentration from 5 to 20%, but not by SP, vasopressin, bombesin or insulin-like growth factor 1. There was some inhibition of CFE by 3/3 normal human bone marrows, IC50s of 30-80 microM, compared with 8 microM for HC12 in 20% FCS. Therefore D-Phe5SP appears to have more potent antiproliferative effects in tumour cells than normal cells, suggesting a role for this analogue in tumour treatment.
神经递质P物质（SP）的类似物可与神经肽受体相互作用，据报道能抑制小细胞肺癌细胞系（SCLC CLs）的生长。我们发现[D-精氨酸1，D-苯丙氨酸5，D-色氨酸7,9，亮氨酸11]P物质（D-苯丙氨酸5SP）能显著抑制10种人类肿瘤细胞系的DNA合成，其中包括6种小细胞肺癌细胞系、1种非小细胞肺癌（鳞状）细胞系、2种卵巢癌细胞系和1种宫颈鳞状癌细胞系，抑制率达50%对照水平（IC50）时的浓度为20 - 50微摩尔。在3种小细胞肺癌细胞系和1种非小细胞肺癌细胞系中，集落形成效率（CFE）呈剂量依赖性抑制，在5%血清中IC50为0.5 - 6.5微摩尔。将小细胞肺癌细胞系HC12暴露于100微摩尔D-苯丙氨酸5SP中1 - 4小时，活细胞数量逐渐减少；在无肽的情况下生长的存活细胞生长速率降低。在将两种小细胞肺癌细胞系暴露于20微摩尔D-Ph5SP 1周的过程中，生长速度比对照培养物慢，而50 - 100微摩尔则完全抑制生长。通过将血清浓度从5%提高到20%，这些抑制作用可部分逆转，但P物质、血管加压素、蛙皮素或胰岛素样生长因子1不能逆转。3种正常人骨髓细胞系的CFE也有一定程度的抑制，IC50为30 - 80微摩尔，而在20%胎牛血清中HC12的IC50为8微摩尔。因此，D-苯丙氨酸5SP在肿瘤细胞中似乎比正常细胞具有更强的抗增殖作用，提示该类似物在肿瘤治疗中可能发挥作用。
