Supply and Formulation

Prior to entering clinical trialS/ adequate drug supplies of pharmaceutical-grade material must be available. This may require the development of bulk chemical synthesis protocols or/ in the case of natural product isolation/ adequate amounts of raw materials 

In Vivo Studies — Efficacy Testing in Animal Models 

A number of animal model systems have been developed to provide tumor microenvironments that mimic the clinical situation. However, there are no perfect animal models for drug development. The adequacy of any specific animal model depends on its validity, selectivity, predictability, and reproducibility (22). In cancer chemotherapy, animal models are selected to simultaneously demonstrate antitumor efficacy and evaluate systemic toxicities in an intact organism. Ideally, the tumor system under study in the animal model should be genetically stable over time, with homogeneous characteristics that mimic human tumor biology. In oncology, a variety of diverse animal models for human tumors have been developed. These models can be broadly categorized in to three 

Although spontaneous tumors closely resemble the human clinical situation, a number of factors make these models poorly reproducible in controlled settings. These include difficulties in adequately staging the tumors, variations in their natural history, and the low yields of animals that actually develop tumors. Consequently, spontaneous tumors have greater utility in the study of carcinogenesis and chemopre-vention, and are somewhat less useful as routine therapeutic models for studying the treatment of established tumors. 

An important advance in preclinical models for anticancer agents was the development of immuno-suppressed mouse strains that allowed for the reproducible implantation and growth of human tumor cells in vivo. The first xenograft of a human colon cancer cell line into immunocompromised nude mice was reported in 1969 by Rygaard and Povlsen (41). 

---