Systemic therapy with cytotoxic drugs is the 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 which 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 which 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 identify
mechanisms of antineoplastic resistance. It is expected that through
such information, drug resistance may be circumvented by rational design
of new non–cross-resistant agents, by novel delivery or combinations of
known drugs and by the development of other treatments which may
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. A list of these general mechanisms of drug
resistance are categorized in .
Considered here are mechanisms involving anatomic, pharmacologic, and
host-drug-tumor interactions which are uniquely pertinent to patients
and to in vivo models of drug resistance, as well as cellular mechanisms
which 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 . Furthermore, multiple independent mechanisms of antineoplastic resistance may coexist in a population of tumor cells.
General Mechanisms of Drug Resistance.
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 which 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.