We previously reported real-time monitoring of cell cycle dynamics of
cancer cells throughout a live
tumor intravitally using a fluorescence ubiquitination cell cycle
indicator (FUCCI). Approximately 90% of
cancer cells in the center and 80% of total cells of an established
tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that
cytotoxic agents killed only proliferating
cancer cells at the surface and, in contrast, and had little effect on the quiescent
cancer cells. Resistant quiescent
cancer cells restarted cycling after the cessation of
chemotherapy. Thus cytotoxic
chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid
tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon
tumor intrinsic chemoresistance (
TIC). We previously demonstrated that
tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent
cancer cells in
tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when
cancer cells were treated with recombinant
methioninase (rMETase), the
cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing
stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent
cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed
cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or
paclitaxel (PTX)
chemotherapy to kill the decoyed and trapped
cancer cells completely prevented or regressed
tumor growth. These results demonstrate the effectiveness of the praradigm of "decoy, trap and shoot"
chemotherapy.