The absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of molecules and membranes that influence this transfer are, therefore, important. The determining characteristics of a drug are its molecular size and shape, degree of ionization, relative lipid solubility of its ionized and nonionized forms, and its binding to tissue proteins. | ). The molecules B7-1 (CD 80) and B7-2 (CD 86) stimulate one such pathway. The B7s, whose expression normally is limited to antigen-presenting cells and other specialized immune effector cells, engage specific receptors (CD-28 and CTLA-4) on the T-cell surface in concert with antigen binding to the T-cell receptor. Subsequently, T-cell activation, cell proliferation, and cytokine production ensue and can lead to the elaboration of antitumor immunity. The absence of a costimulatory signal at the time of T-cell receptor engagement is not a neutral event; rather, it results in the development of tumor-specific anergy, not mere failure to activate the T cell. Thus, the simple presence of antigens in tumor cells would be expected to produce an immune-tolerant state rather than an immune-responsive state if costimulatory events do not take place. In effect, this is what is seen in most clinical situations where human tumors grow apparently unimpeded by host immune mechanisms. When some tumor cells are provided with costimulatory molecules, effective T-cell activation takes place. This has been demonstrated by ectopic expression of B7 on tumor cells; these genetically engineered tumor cells then are used to stimulate an immune response to the parental tumor cell line.
