Bepler G
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Cancer Invest. 1994;12(5):491-6. doi: 10.3109/07357909409021409.
T alpha 1, a 28-amino-acid peptide, is derived from PT alpha, which is an intracellular, nonsecretory protein of unknown function. Both T alpha 1 and PT alpha are found in the blood of normal individuals. Subcutaneous and intramuscular injections of T alpha 1 in doses up to 9.6 mg/m2 are tolerated without side effects, and 0.9 mg/m2 injections raise the serum level approximately 30-fold after 1 hr of administration, which slowly returns to baseline within 24 hr. In vitro, and perhaps in vivo, T alpha 1 restores normal T-cell function. It increases IL-2 production and IL-2 receptors in normal mitogen-stimulated T cells and stimulates IL-3 production in immunocompromised mice. The dose-response relationship for these effects is not linear and may be bimodal. T alpha 1 binds to VIP receptors and inhibits in vitro and xenograft growth of non-SCLC cell lines. In patients with nonbulky carcinomas who have received standard therapy, T alpha 1 is possibly effective in prolonging the time to relapse and in improving survival. At present there is a great need to clearly define the clinical role of T alpha 1 in cancer patients. A major problem encountered in studies with T alpha 1 will, however, be the present lack of knowledge with regard to its mechanism in effecting tumor growth. It is not at all clear whether its immunomodulatory functions, its interaction with VIP receptors, or none of these mechanisms are related to its antineoplastic activities. In addition, the apparent nonlinear dose-response relationship will make it difficult to choose a reasonable dosing schedule for clinical trials. This is particularly apparent in light of the experimental animal data summarized above where a tumor response was seen at doses of 4 micrograms/kg and 400 micrograms/kg but not at 0.4 microgram/kg and 40 micrograms/kg. This dose range could conceivably be given to humans since 9.6 mg/m2, the maximum dose given to humans without major side effects to date, is roughly equivalent to 250 micrograms/kg. At this time a reasonable clinical approach would be a well-designed risk factor stratified phase III clinical trial using 0.9 mg/m2 T alpha 1 subcutaneously twice a week compared to a control group to substantiate the data reported by Schulof et al. Before such data are available, T alpha 1 should not be used in clinical oncology.
Tα1是一种由28个氨基酸组成的肽，它来源于PTα，PTα是一种细胞内非分泌蛋白，功能未知。在正常个体的血液中可发现Tα1和PTα。皮下和肌肉注射高达9.6mg/m²剂量的Tα1耐受性良好，无副作用，注射0.9mg/m²在给药1小时后可使血清水平升高约30倍，并在24小时内缓慢恢复至基线水平。在体外，或许在体内，Tα1可恢复正常的T细胞功能。它可增加正常有丝分裂原刺激的T细胞中白细胞介素-2（IL-2）的产生和IL-2受体，并刺激免疫受损小鼠中IL-3的产生。这些作用的剂量-反应关系不是线性的，可能是双峰的。Tα1与血管活性肠肽（VIP）受体结合，并抑制非小细胞肺癌（NSCLC）细胞系的体外生长和异种移植生长。在接受标准治疗的非大块癌患者中，Tα1可能有效地延长复发时间并提高生存率。目前，非常需要明确Tα1在癌症患者中的临床作用。然而，在Tα1的研究中遇到的一个主要问题是目前对其影响肿瘤生长的机制缺乏了解。其免疫调节功能、与VIP受体的相互作用，或者这些机制都与它的抗肿瘤活性是否相关，根本不清楚。此外，明显的非线性剂量-反应关系将使得难以选择合理的给药方案用于临床试验。鉴于上述实验动物数据，这一点尤为明显，在该数据中，在4μg/kg和400μg/kg剂量下观察到肿瘤反应，而在0.4μg/kg和40μg/kg剂量下未观察到。由于9.6mg/m²（迄今为止给予人类无重大副作用的最大剂量）大致相当于250μg/kg，这个剂量范围理论上可以给予人类。此时，一种合理的临床方法将是设计良好的风险因素分层III期临床试验，与对照组相比，每周两次皮下注射0.9mg/m²Tα1，以证实舒洛夫等人报告的数据。在获得此类数据之前，Tα1不应在临床肿瘤学中使用。
