Drug Resistance and Its Clinical Circumvention

basis for most effective treatments of disseminated cancers. Additionally, adjuvant chemotherapy can offer a significant survival advantage to selected patients, following the treatment of localized disease with surgery or radiotherapy, presumably by eliminating undetected minimal or microscopic residual tumor. However, the responses of tumors to chemotherapeutic regimens vary, and failures are frequent owing to the emergence of drug resistance. Patterns of treatment response and tumor sensitivity are conveniently divided into three groups. First, with modern treatments, prompt cytoreduction and cures are common for some intrinsically drug-sensitive tumors, such as childhood acute lymphoblastic leukemia (ALL), Hodgkin’s disease, some non-Hodgkin’s lymphomas, and testicular cancer. A second group comprises tumors such as breast carcinomas, small-cell lung cancers, and ovarian carcinomas, which are also usually highly responsive to initial treatments but more often become refractory to further therapy. Relapses in either group of tumors, particularly during or shortly after the completion of therapy, generally herald the emergence of tumor cells that are resistant to the antineoplastic agents used initially and often to drugs to which the patient was never exposed. Therefore, success with conventional salvage chemotherapies has been limited. Finally, a third common pattern of drug sensitivity is found in tumors that are intrinsically resistant to most chemotherapeutic agents. This group is represented by malignancies such as non–small-cell lung cancers, malignant melanoma, and colon cancer. For these tumors, the number of active antineoplastic agents is low, and significant chemotherapeutic responses are effected only in a minority of cases. The phenomenon of clinical drug resistance has prompted studies to clarify mechanisms of drug action and to identify mechanisms of antineoplastic resistance. It is expected that through such information, drug resistance may be circumvented by rational design of new non–crossresistant agents, by novel delivery or combinations of known drugs and by the development of other treatments that might augment the activity of or reverse resistance to known antineoplastics. Multiple mechanisms of antineoplastic failure have been identified using in vitro (tissue culture) and in vivo (animal and xenograft) models of antineoplastic resistance. Table 48-1 categorizes these general mechanisms of drug resistance. Considered here are mechanisms involving anatomic, pharmacologic, and host– drug–tumor interactions that are uniquely pertinent to patients and to in vivo models of drug resistance, as well as cellular mechanisms that can be described at the molecular level. These mechanisms are frequently interrelated as, for example, altered gene expression must ultimately underlie most of the cellular and biochemical mechanisms listed in Table 48-1. Furthermore, multiple independent mechanisms of antineoplastic resistance may coexist in a population of tumor cells. While mechanisms of drug resistance have been largely determined in experimental systems, many have been implicated in at least some examples of clinical chemotherapeutic failure. Evidence that bears upon these mechanisms of resistance as well as strategies to circumvent them are discussed below. First, we discuss the general mechanisms of cellular drug resistance and then some specific examples in the sections that follow. Additionally, the important concept of resistance to multiple antineoplastic agents, resistance to specific classes of drugs, and resistance mechanisms unique to in vivo situations are discussed.