PHARMACOLOGIC AND PHASE I STUDIES OF NEW AGENTS FOR THE TREATMENT OF HUMAN SOLID

新型抗癌药的药物开发通常涉及到从生物化学和分子水平对药物作用机制的广泛研究。在人类中，对Ne分子实体的初步研究传统上将药物药代动力学和药效学的测量纳入早期I期研究。然而，由于在研究人类受试者时存在明显的技术和后勤困难，药物效应的细胞内测量并不常见。此外，有希望的新药在早期临床试验中未能产生抗癌活性的确切原因往往是未知的。只有通过设计科学合理的临床试验，将传统的药代动力学终点与细胞内药效学测量相结合，我们才有希望更好地了解新药在人类身上的精确作用。这种方法有望阐明为什么我们的临床试验中正在研究的新疗法有效或无效。目前，我们实验室正在将气相色谱、液质联用等分析技术应用于I期临床研究。这些研究包括使用嘧啶新陈代谢的抑制剂，如苯氧尿嘧啶，对氟化的嘧啶进行生物化学调节的研究。其他正在研究或计划中的药物包括17-烯丙氨基-17-去甲氧基格尔达那霉素，一种针对头部休克蛋白的新型药物，以及染料木素，一种从大豆中提取的具有癌症预防和生长抑制特性的天然产品。最后，由于在第一阶段研究中登记的患者使用替代药物的潜在影响，我们正在检查在我们的研究人群中流行的替代药物的流行率和类型。-结直肠癌，

Drug development of new anticancer agent typically involved extensive studies of drug mechanisms of action at the biochemical and molecular level. In humans, initial studies of ne molecular entities traditionally incorporate measurement of drug pharmacokinetics and pharmacodynamics into early phase I studies. However, intracellular measurement of drug effects are less common due to obvious technical and logistical difficulties in study human subjects. Furthermore, the exact reasons why promising new drugs fail to generate anticancer activity in early clinical trials are frequently unknown. Only by designing scientifically sound clinical trials that combine traditional pharmacokinetic endpoint with intracellular pharmacodynamic measurements can we hope to obtain a better understanding of the precise actions of new drugs in humans. This approach will hopefully elucidate why new treatments under study in our clinical trial do or do not work. Currently, our laboratory is applying analytic techniques such as gas and liquid chromotagraphy with mass spectroscopic detection to phase I clinical studies. These include studies of biochemical modulation of fluorinated pyrimidines, using inhibitors of pyrimidine metabolism, such as eniluracil. Other ongoing or planned agents under study include 17-allylamino-17-demethoxygeldanamycin, a novel agent that targets head shock proteins, and genistein, a natural product derived from soy beans with cancer preventative and growth inhibitory properties. Finally, because of the potential impact of the use of alternative medicines in patients enrolled in phase I studies, we are examining the prevalence and types of alternative medicine popular in our study populations. - colorectal cancer,