Authors: Ming C. Liau, Christine L. Craig, Linda L. Baker.
The objective of this study is to develop cancer drugs effective against cancer stem cells (CSCs) to save cancer patients. Cancer incidence and mortality keep on increasing during the past 50 years, which is an indication that the health profession is not handling cancer therapy right. Cancer therapy got to a bad start to rely on cytotoxic drugs to kill cancer cells (CCs) and to set up disappearance of tumor as a diagnostic criterion for the evaluation of cancer drugs. Cancer drugs developed by the health profession in the past can only benefit a minority of cancer patients in the early stage whose chemo-surveillance has not been fatally damaged, whereas these drugs cause the fatality of a majority of cancer patients in the advanced stage whose chemo-surveillance has been fatally damaged. Thus, cytotoxic drugs and radiation put up by the health profession are responsible for the ever- increasing cancer mortality.
Cancer evolves as a consequence of wound unhealing due to the collapse of chemo-surveillance. Chemo-surveillance is the nature’s creation to ensure perfection of wound healing. Wound healing requires the proliferation and the terminal differentiation of progenitor stem cells (PSCs). Methylation enzymes (MEs) of PSCs are abnormal due to association with telomerase which is expressed in PSCs. MEs play a pivotal role on the regulation of cell replication and differentiation. The association of MEs with telomerase tilts the regulation in favor of cell growth. The nature creates chemo-surveillance as an allosteric regulation to prevent unnecessary build-up of cells with abnormal MEs. The collapse of chemo-surveillance disrupts wound healing and forces PSCs to evolve into cancer stem cells (CSCs) by silencing TET-1 enzyme to escape contact inhibition that limits the extent of PSCs to proliferate. The evolution of CSCs is the initial phase of cancer evolution closely related to wound unhealing. Subsequent cancer progression through chromosomal abnormalities such as translocations to activate oncogenes or deletions to inactivate suppressor genes is also due to wound unhealing, but is not as tightly related to wound unhealing as CSCs. Induction of terminal differentiation is the only option to solve the problem of CSCs which are needed to heal the wound. Elimination of CCs can be done by induction of differentiation or cell killing, which are not needed to heal the wound.
Myelodyspleastic syndromes (MDS) are typical diseases to illustrate cancer evolution due to wound unhealing. MDS are triggered by disorders such as chronic infections or wounds which prompts the patients to yield a high level of cytokines. Tumor necrosis factor (TNF) among such cytokines is most closely related to the development of MDS. It causes the apoptosis of bone marrow stem cells and cachexia symptoms to result in the collapse of chemo-surveillance and the evolution of CSCs. MDS are diseases attributable entirely to CSCs. CDA-2, Vidaza and Decitabine are the three drugs approved by the Chinese FDA for the therapy of MDS. Vidaza and Decitabine are also approved by the US FDA for the therapy of MDS. These drugs achieve MDS therapy by the induction of terminal differentiation of CSCs. MDS can be used to screen drugs effective against CSCs essential to save cancer patients.
CSCs are the dominant issue of metastatic, unresponsive and recurrent cancers. Induction of terminal differentiation is the only option for the solution of CSCs, and the solution of CSCs is essential to save cancer patients in desperate situation. CDA formulations are, therefore, the only drugs that can come to the rescue of such patients.
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