The Cancer Cell-Kill Paradigm and Beyond

Abstract

According to NCI, “Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues” [318]. In fact, most definitions use “uncontrolled” proliferation or growth at their core. More generic terms include tumors and neoplasms, though they can be benign, pre-malignant, or malignant. Implicit in the terms tumor (abnormal mass) and neoplasm (new growth) is the notion that these processes, particularly in their malignant variety, like invading bacteria, are inherently different from the host and must be thoroughly eradicated in order to prevent metastases and death. The application of the infectious disease model to cancer steered cancer research, diagnosis, treatment, and outcome assessment strategies towards both surgical excision of early-stage disease and the cancer cell-killing paradigm to eradicate advanced cancer, which is the focus of this chapter. 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 [319], a misconceived generalization that drove drug use for decades, to tumor-specific antigens targetable for therapy [320], an illusion not yet abandoned. As decried in a recent article, “It could be argued that 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” [321]. The second corollary is the concept of “cytotoxicity” (e.g., cell killing) of rapidly dividing cells introduced to describe the quintessential property that drugs must exhibit in order to be successful in the treatment of disseminated cancer. However, how these drugs were to kill cancer cells preferentially 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, microRNA that control the expression of most human genes, or defective cell death pathways that confer a survival advantage to cancer cells. From this flawed concept about cancer treatment, an entire lexicon emerged in attempts to explain empirical clinical observations. For example, the tendency of some tumors to outgrow adjacent normal tissues, a phenomenon that can be slowed and sometimes stopped by anti-cancer drugs, suggested a pivotal role for the cell cycle in tumor growth and anti-cancer drug activity. Thus, cancer drugs were classified as cell cycle dependent if they acted upon one of the phases of the cell cycle, and cell cycle independent if their anti-tumor activity was independent of the cell cycle. The former, in turn, were classified as S-specific (drugs such as the antimetabolites and anti-purines that inhibit DNA synthesis), M-phase dependent (drugs that arrest mitosis, such as Vinca alkaloids, Podophyllotoxins and Taxanes), or G₁- and G₂-phase dependent, such as Corticosteroids and Asparaginase, and Bleomycin and Topotecan, respectively. Cell-cycle independent drugs included the alkylating agents, such as Busulfan, Melphalan, and Chlorambucil that, by crosslinking guanine nucleobases on the DNA, prevent uncoiling and replication of the double helix, hence the cell division. Mechanism of action to a large degree determined the type of toxicity. Likewise, it was quickly discovered that anti-tumor activity was dose-dependent, but, given its non-specificity, dose escalation was limited by type and severity of toxicity resulting from drug effect on normal cells. Thus, in order to enhance anti-tumor activity while reducing toxicity, drugs with different mechanisms of action were combined and administered intermittently to reduce toxicity on normal tissues, especially the high turnover bone marrow, and enable time to recover from toxicity between treatment cycles. Perhaps the most successful example of this approach was the MOPP (Nitrogen mustard, Vincristine, Prednisone, and Procarbazine) chemotherapy regimen for Hodgkin’s disease that proved curative in most cases [322]. However, this early success was seldom replicated despite a myriad of clinical trials launched to test a variety of intermittent combination chemotherapy regimens in many types of cancers over the ensuing four decades.