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Gmeiner. Cancer Drug Resist 2019;2:994-1001 I http://dx.doi.org/10.20517/cdr.2019.95 Page 999

that different approaches may be required to enhance the activities of fluoropyrimidine polymers relative to
CPT derivatives, or alternative nucleoside analogs. Top1-directed activities of nucleoside analogs contribute
to their clinical activities. Comprehensive, mechanism-based combination therapy can enhance these
activities, and further improve outcomes.

CONCLUSION
Top1 poisons continue to be among the world’s most important anti-cancer drugs. In addition to being the
sole target for CPT derivatives, Top1 is an important target for agents that induce DNA damage including
ionizing radiation, reactive oxygen species, or formation of covalent adducts. Top1 is also target for
nucleoside analogs such as AraC and GEM. Dual targeting of TS/Top1 by DNA-directed fluoropyrimidines
such as F10 shows promising activity in pre-clinical cancer models. TS/Top1 dual targeting is distinct from
Top1 poisoning by CPT derivatives because Top1cc repair occurs under thymineless conditions and shows
different dependence on Top1cc repair pathways. A challenge in coming years will be how to use the Top1
poisoning activity of nucleoside analogs for improved care in the context of personalized therapy taking
into account patient-specific expression of DNA repair pathways.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
Research reported in this publication was supported by the National Cancer Institute’s Cancer Center
Support Grant (P30CA012197) issued to the Wake Forest Baptist Comprehensive Cancer Center. Gmeiner
WH is supported by NIH grant (NIH-NCI R21 CA218933).

Conflicts of interest
The author declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2019.

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