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  • The present findings suggested that

    2020-02-12

    The present findings suggested that nsEP inhibited CPG2 via deprivation of zinc ions, with no effect on apoenzyme integrity. Zinc may be removed from CPG2 by the electric forces. Within CPG2, each zinc ion was coordinated by one histidine, one glutamate and one aspartate [6]. The nsEP field can alter the free-energy profile of histidine [4], which relaxed the covalent bonds, thus releasing a zinc ion. As pulse duration was a determinant of the electric energy [10], longer pulses would lead to lower levels of zinc in CPG2, resulting in a lower activity. The binding of zinc within a protein with tertiary structure differed from that within CPG2; whether nsEP caused the zinc eviction in those proteins therefore should be explored. Similarly, nsEP may deactivate a protein with quaternary structure but without prosthetic groups, via other mechanisms such as the disassembly and conformation changes. CPG2 can release an active drug from a nontoxic prodrug (i.e., prodrug therapy). Because of enzymolysis, prodrugs became rapidly activated, leading to a high level of active drugs within the cancer; the leak of active drugs back into the circulation can cause systemic toxicity [11]. The present data suggested that nsEP modulate CPG2 activity, which may be useful to assist prodrug therapy. Further, nsEP was previously reported to produce anticancer effects [1], [12]. Thus, the combination of these two modalities may improve therapeutic efficacy and decrease toxicities.
    Conclusion
    Acknowledgments This work was supported with a grant from the State Ministry of Education (SRFDP 20135503130002).
    Introduction Cancer is one of the leading causes of mortality with 8.2 million deaths and 14.1 million new cases worldwide (Cancer Research UK 2012). Although survival rates for certain cancers can be 98%, there are other types which only reach 1%. Therefore there remains an urgent need to develop new treatments. It has been long established that most chemotherapeutic agents lack specificity for cancer cells. The utilisation of monoclonal methoxy directed at tumour associated antigens to deliver drugs or radiation to tumours for diagnosis and therapy improved specificity. These antibody-drug conjugates needed to be internalised for the drug to be released intracellularly to exert its effect and success was limited for most epithelial cancers due to the heterogeneous nature of antigen expression [1] and other factors such as poor drug to antibody ratio and inadequate intracellular trafficking. It was during these times almost 30years ago that antibody directed enzyme prodrug therapy (ADEPT) was first proposed [2], [3], [4] to overcome some of the limitations of early antibody-drug conjugates. ADEPT did not need internalisation but aimed to generate drug in the extracellular areas of the tumour. However, it should be noted that whereas, ADEPT is still an experimental approach and mainly pursued by small academic groups at random, thanks to the consistent and determined effort from pharmaceutical industry, the field of antibody-drug conjugates [5] (ADC) has made immense progress towards generating molecules that showed greater clinical benefit which resulted in FDA approval of two compounds, Adcetris [6]and Kadcyla [7] and many more are in clinical development [8]. However, many challenges remain with both ADC and checkpoint inhibitor therapies. Main limitation of the current ADC molecules is drug resistance and antigen downregulation [9]. Although remarkable tumour responses have been observed with checkpoint inhibitors, these are associated with immune related toxicity including autoimmune disease [10], [11]. Therefore, alternative forms of therapies still need to be explored. Enzyme and prodrug systems provide an attractive approach for cancer therapy [12], [13], [14]. Earlier studies tried to explore the possibility of utilising enzymes present within tumours to convert low toxicity prodrug to a cytotoxic agent but no unique tumour specific enzymes were found [15]. Thus the ADEPT concept was formed (Fig. 1). It was proposed that monoclonal antibodies could be used to deliver unique enzymes specifically to tumours where they could methoxy convert many molecules of prodrugs to potent cytotoxic agents within tumours [2]. Hence a higher concentration of drug could be achieved than possible by direct administration. The drug would be generated extracellularly and being a small molecule could diffuse throughout the tumour mass also killing the cells not expressing the antigen via a by-stander effect [16].