Some lymphomas appear to originate from more than a single clone and continue to evolve in cell structure and in responsiveness to therapy, as do cancers that arise from a single clone. An understanding of the mechanisms responsible for the continued diversification of tumor cell populations that leads to tumor progression presents the principal challenge to the development of new cancer treatments. The cells that overgrow the tumor population not only are resistant to the agents used but also tend to be resistant to other drugs, many of which have dissimilar mechanisms of action. This phenomenon, called pleiotropic drug resistance or multidrug resistance, may account for much of the drug resistance that occurs in previously treated cancer patients. This mechanism has been most extensively investigated in tumors that are resistant to methotrexate both in vitro and in vivo.
Methotrexate acts by inhibiting the action of the enzyme tetrahydrofolate reductase.
Amplification of the gene that encodes tetrahydrofolate reductase causes overproduction of the enzyme, thus leading to methotrexate resistance. In addition to gene amplification, changes in the rate of transport of methotrexate into cancer cells and in the structure of dihydrofolate reductase can contribute to clinical resistance to this drug. Gene amplification can also be involved in the phenomenon of multidrug resistance. Multidrug resistance appears to be linked to overexpression of a cell membrane glycoprotein, termed P-glycoprotein, on the surface of cancer cells. This cell membrane glycoprotein serves as a transporter for the efflux of noxious substances, such as chemotherapeutic drugs.