Pierce D F, Coffey R J
Dept. of Surgery, Vanderbilt School of Medicine, Nashville, TN 37232-2730.
Am Surg. 1994 Jan;60(1):18-25.
We have developed a mouse model to utilize the specific regulatory effects of Transforming Growth Factor Beta-1 (TGF beta 1), the prototype for a family of growth inhibitory cytokines. A vital factor in the regulation of normal cellular growth for many cell types, TGF beta 1 prevents proliferation by reversibly arresting cells at the G1/S border of the cell cycle, thus delaying DNA synthesis and cell division. Since the dose of cytotoxic chemotherapy is limited by its adverse effects on bone marrow and gut cells, we proposed that a TGF beta 1-induced block at G1/S would diminish the S phase toxicity of high dose cytarabine (ara-C). The dosage of ara-C required to kill 90 per cent of 4-week old DBA/2 males was determined to be 3200 mg/kg every 12 hours x 2. Pretreatment with TGF beta 1 6-24 hours before the first dose of ara-C proved to be significantly protective; 8/9 TGF beta 1-pretreated mice survived versus 1/9 treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 10.89 P = 0.001). A second experiment confirmed this effect; TGF beta 1 pretreatment for 6-24 hours protected 9/9 versus 0/9 survivors in the group treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 18.0, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
我们构建了一种小鼠模型，以利用转化生长因子β-1（TGFβ1）的特定调节作用，TGFβ1是生长抑制细胞因子家族的原型。作为许多细胞类型正常细胞生长调节中的一个重要因子，TGFβ1通过使细胞在细胞周期的G1/S边界可逆性停滞来阻止增殖，从而延迟DNA合成和细胞分裂。由于细胞毒性化疗的剂量受其对骨髓和肠道细胞的不良反应限制，我们提出TGFβ1诱导的G1/S期阻滞会降低高剂量阿糖胞苷（ara-C）的S期毒性。杀死90%的4周龄DBA/2雄性小鼠所需的ara-C剂量确定为每12小时3200mg/kg，共2次。在首次给予ara-C前6 - 24小时用TGFβ1预处理显示出显著的保护作用；8/9经TGFβ1预处理的小鼠存活，而在TGFβ1处理3小时或更短时间或仅用ara-C处理的小鼠中，存活的为1/9（χ2 = 10.89，P = 0.001）。第二项实验证实了这一效果；在TGFβ1处理3小时或更短时间或仅用ara-C处理的组中，经6 - 24小时TGFβ1预处理的小鼠有9/9存活，而未预处理的组无存活（χ2 = 18.0，P < 0.001）。（摘要截短为250字）
