Nucleoside analogs are an important class of
anticancer agent that historically show better efficacy against hematological
cancers versus solid
tumors. This report describes the development and characterization of a new class of
nucleoside analog that displays anticancer effects against both hematological and adherent
cancer cell lines. These new analogs lack canonical hydrogen-bonding groups yet are effective
nucleotide substrates for several high-fidelity
DNA polymerases. Permutations in the position of the non-hydrogen-bonding functional group greatly influence the kinetic behavior of these
nucleosides. One particular analog designated 4-nitroindolyl-2'-deoxynucleoside
triphosphate (4-NITP) is unique as it is incorporated opposite C and T with high catalytic efficiencies. In addition, this analog functions as a nonobligate chain terminator of
DNA synthesis, since it is poorly elongated. Consistent with this mechanism, the corresponding
nucleoside, 4-nitroindolyl-2'-deoxynucleoside (4-NIdR), produces antiproliferative effects against
leukemia cells. 4-NIdR also produces
cytostatic and cytotoxic effects against several adherent
cancer cell lines, especially those that are deficient in mismatch repair and p53. Cell death in this case appears to occur via mitotic catastrophe, a specialized form of apoptosis. Mass spectroscopy experiments performed on
nucleic acid isolated from cells treated with 4-NIdR validate that the non-natural
nucleoside is stably incorporated into
DNA. Xenograft mouse studies demonstrate that administration of 4-NIdR delays
tumor growth without producing adverse side effects such as
anemia and
thrombocytopenia. Collectively, the results of in vitro, cell-based, and animal studies provide evidence for the development of a novel
nucleoside analog that shows enhanced effectiveness against solid
tumors.