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,