Multiple drug resistance, the MDR gene, and the law of maximum perversity as it applies to oncology: An hypothesis

The so‐called Law of Maximum Perversity, generally stated, says that when more than one outcome is possible, that which is the more adverse is the outcome most likely to occur. In medical oncology, the most obvious expression of this law is the fact that all the neoplasms that are most sensitive to cytotoxic drugs and are most curable by chemotherapy, are rare and in numerical terms are not important as causes of cancer‐related deaths. Conversely, the most commonly encountered neoplasms that make up the bulk of oncologic practice and that cause over 90 per cent of cancer‐related deaths, are all relatively resistant to cytotoxic agents and are virtually never curable by chemotherapy administered in standard (i.e. non‐transplant) doses. It is postulated that the biological properties and the normal tissue distribution of the multidrug resistance (MDR) gene and its product p‐170 glycoprotein explain the observed incidences and distribution of tumours that are sensitive or insensitive to cytotoxic agents. The normal role of MDR is to protect cells from environmental carcinogens, and the tissues that are most at risk, and most richly supplied with MDR, will produce drug‐resistant neoplasms. Current attempts at MDR reversal may facilitate the treatment of some tumours that are resistant to multiple drugs but may cause severe toxic effects as a consequence of abrogating the largely unknown physiologic functions of P‐170.