In: Chemotherapy23 Nov 2014
Identification of New Chemotherapeutic Agents
For the past 3 decades, the major strategies of preclinical testing of agents with potential anticancer activity in humans has depended on the use of mice bearing transplantable tumors (predominantly leukemias) of murine origin. This effort has utilized enormous resources of time, talent and money, and the results of screening several hundred thousand compounds have been disappointing. Relatively few useful drugs that have widespread utilization have been identified. The reasons for these results are complex, but include the failure of mouse leukemia models to correctly identify agents useful in treating human malignancies. In addition, even when such agents are identified, the type and varieties of human malignancies in which they may be utilized are not readily apparent. These experiences have led to a complete revamping of the screening process by the Developmental Therapeutics Program at the National Cancer Institute. A large number of human tumor cell lines have been grouped into disease-oriented panels and have been extensively characterized. comments
A panel of 30 lung cancer lines representing 8 lung cancer pathologies, as well as more than 70 lines representing 10 other categories of common human malignancies has been established. Each panel represents a spectrum of tumor subtypes and they exhibit a wide range of sensitivities to commonly utilized chemotherapeutic agents. A semi-automated protein assay is utilized to screen the panels with potential new agents (most from natural sources), as well as to confirm the activity of agents or analogues selected by other methods. Since both the MTT and the protein assay provide sensitive and reproducible indices of growth and drug sensitivity in individual lines over the course of many passages, they are especially suitable for initial screening. Compounds identified as having disease-specific activities are further tested in human xenograft models and by other tests including murine systems and clonogenic assays. Similar approaches are being utilized to screen for anti-AIDS agents, as well as to test some biologic response modifiers. This new screening method, while untested, appears to be a more scientific strategy than previous ones, and, hopefully, one that will result in the identification of new agents useful in treating one or more types of lung cancer.
Where Are We, and Where Do We Go?
From the information provided above, certain conclusions can be made. Cell lines reflect the chemosensitivity profiles of the tumors from which they were derived. Animal models and cell lines are useful for biologic studies and for the screening of new drugs. Disease-oriented panels of human cell lines offer a new and exciting alternative to the disappointing methods previously used. In vitro assays for selecting individualized therapy are difficult to perform correctly, are very labor intensive, and remain largely investigational methods. Currently, they are not suitable for general application or for commercialization. Such methods, even with technical improvements, may not be generally useful until we have better anticancer drugs. Over-expression of F-gly-coprotein is not the major cause of drug resistance, either acquired or de now, in lung cancer.
It is much harder to predict the future. In my opinion, the current methodologies are relatively crude, technically difficult, and are of modest direct clinical use. Discovery of more efficacious drugs, development of newer therapeutic modalities and a better understanding of drug resistance will probably be required before predictive assays can achieve widespread application.
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