The cancer cell-kill paradigm and its corollaries

Implicit in the term neoplasm or “new growth” is the notion that cancer, like invading bacteria, is inherently different from the host and must be thoroughly eradicated in order to prevent recurrences and death. The application of the infectious disease model to cancer steered cancer research, diagnosis, treatment, and outcome assessment strategies towards the cancer cell-killing paradigm. That is, like invading bacteria, cancer must be eradicated before it overwhelms the host. From this basis, two major practical corollaries followed. The first is that cancer research has been oriented towards the search for therapeutically exploitable differences between cancer and normal cells, guided by successive hypotheses ranging from excessive cancer cell proliferation, a misconceived generalization that drove drug use for decades, to tumor-specific antigens targetable for therapy; an illusion not yet abandoned. As decried in a recent article 3, “medical treatment of cancer for most of the past century was like trying to fix an automobile without any knowledge of the internal combustion engines or, for that matter, even the ability to look under the hood”. The second corollary is the concept of ”cytotoxicity” (or cell killing) that was introduced to describe the quintessential property that drugs must exhibit in order to be successful in the treatment of disseminated cancer. However, how were these drugs to preferentially kill cancer cells while sparing normal cells was never adequately explored nor fully explained. The notion of cell-killing as the cornerstone of cancer treatment became untenable when the carcinogenic process was shown to involve oncogenes that promote cell growth, mutated tumor suppressor genes that fail to counteract cancer-promoting oncogenes, defective DNA repair genes that enable replication and propagation of unstable genomes, or faulty cell death pathways that confer a survival advantage to cancer cells.