Thomas M G, Tebbutt S, Williamson R C
Department of Surgery, Royal Postgraduate Medical School, Hammersmith Hospital, London.
Gut. 1992 Dec;33(12):1660-3. doi: 10.1136/gut.33.12.1660.
Like calcium, vitamin D may protect against colorectal neoplasia as it reduces epithelial cell proliferation and induces differentiation. Although its therapeutic use is limited by its effects on calcium metabolism, analogues such as calcipotriol produce little hypercalcaemia. Stathmokinetic and immunohistochemical techniques were used to study the effect of 1,25 (OH)2 D3 and its analogues on cell proliferation in human rectal mucosa and a colon cancer cell line. Paired sigmoidoscopic biopsy specimens were obtained from 17 control patients and five patients with familial adenomatous polyposis. Explants were established in organ culture, with or without the addition of vitamin D. Proliferation was assessed using (1) metaphase arrest to determine the crypt cell production rate (CCPR) and (2) Ki-67 monoclonal antibody directed against an antigen present in proliferating cells. 1,25 (OH)2 D3 in concentrations of 1 microM-100 pM (10(-6)-10(-10) M) reduced the CCPR (cells/crypt/hour) from 4.74 to 2.15-2.67 (p < 0.001), and the Ki-67 labelling index from 7.28-3.74 (p < 0.01). Likewise, vitamin D2, 10 nM (10(-8) M) reduced the CCPR from 4.74-2.74 (p < 0.05) and calcipotriol from 4.86-2.38 (p < 0.05). In familial adenomatous polyposis patients 1,25 (OH)2 D3 100 pM (10(-10) M) halved the CCPR from 8.75-4.22. Calcipotriol (10(-5) M to 10(-9) M) produced a clearcut dose response inhibition of HT-29 cell growth. Thus, vitamin D and its metabolites inhibit proliferation in normal and premalignant rectal epithelium and suppress growth in a colorectal cancer cell line.
与钙一样，维生素D可能预防结直肠肿瘤形成，因为它可减少上皮细胞增殖并诱导分化。尽管其治疗用途因对钙代谢的影响而受到限制，但诸如骨化三醇之类的类似物很少引起高钙血症。采用有丝分裂制动和免疫组化技术研究1,25(OH)₂D₃及其类似物对人直肠黏膜和结肠癌细胞系细胞增殖的影响。从17名对照患者和5名家族性腺瘤性息肉病患者获取配对的乙状结肠镜活检标本。将外植体置于器官培养中，添加或不添加维生素D。使用(1)中期阻滞来确定隐窝细胞产生率(CCPR)，以及(2)针对增殖细胞中存在的一种抗原的Ki-67单克隆抗体来评估增殖情况。浓度为1微摩尔/升-100皮摩尔/升(10⁻⁶-10⁻¹⁰摩尔/升)的1,25(OH)₂D₃将CCPR(细胞/隐窝/小时)从4.74降至2.15-2.67(p<0.001)，并将Ki-67标记指数从7.28降至3.74(p<0.01)。同样，10纳摩尔/升(10⁻⁸摩尔/升)的维生素D₂将CCPR从4.74降至2.74(p<0.05)，骨化三醇则从4.86降至2.38(p<0.05)。在家族性腺瘤性息肉病患者中，100皮摩尔/升(10⁻¹⁰摩尔/升)的1,25(OH)₂D₃使CCPR从8.75减半至4.22。骨化三醇(10⁻⁵摩尔/升至10⁻⁹摩尔/升)对HT-29细胞生长产生明显的剂量反应抑制。因此，维生素D及其代谢产物抑制正常和癌前直肠上皮细胞的增殖，并抑制结肠癌细胞系的生长。
