Because the currently used anticancer drugs are generally not selective enough to cause total tumor eradication, we often find that the initially successful chemotherapy is followed by recurrence of tumor growth, possible due to the development or expression of existing drug resistance. Such expressed or acquired resistance may be the result of gene amplification, or the cell's ability to repair drug induced damage, or because of the presence of a number of different clones of cells within the tumor all having different drug and radiation sensitivities. In addition, treatments with anticancer drugs may in themselves induce changes within a tumor cell population, and that may result in an altered response expressed by the surviving cells to future drug exposures. It is also possible that multiple clones present within the same tumor could influence each other's growth rates and responses to treatment. Using various animal and human tumor lines in our in vitro studies have shown that sensitivity to a given agent may be expressed differently by various clones of a tumor line; that a single treatment with an agent may change the inherent sensitivity of a cell population--indeed it may even select or produce new and different clones which exhibit new growth properties and resistance; and that if one treats long enough with a particular agent or combination of agents, sensitive cells are killed and resistance becomes the predominant response to drug therapy. The possibility that human tumor cells may also repair drug-induced damage in vivo (thereby resulting in recovery and regrowth of the tumor) is also an expression of resistance and could lead to failure of therapy. It is important to continue and expand such studies of human tumor cells in culture. It will be the purpose of this proposal to characterize the heterogeneous cellular responses of tumor clones to anticancer drugs and radiation; and to determine what role factors such as DNA content, ploidy, repair of damage, and prior treatments play in the heterogeneity of tumors. The significance lies in the characterization of these expressions of resistance for a variety of agents, the identification of the mechanisms involved and the means of inhibiting them. Ultimately these model systems provide an excellent means of testing the multiple drug and radiation treatment schedules eventually used in human tumor therapy.
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