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. Author manuscript; available in PMC: 2022 Apr 12.
Published in final edited form as: Cancer Cell. 2021 Apr 12;39(4):566–579.e7. doi: 10.1016/j.ccell.2021.02.014

Figure 2: Concurrent inhibition of ATR and TOP1 exacerbates replication stress and DNA damage.

Figure 2:

A) Schematic illustrating the comet assay (single cell gel electrophoresis) for the detection of DNA damage and specified imaging outcomes, highlighting increased DNA strand breaks caused by the combination of M6620 and topotecan. B) Schematic illustrating the combing assay (spatiotemporal analysis of DNA replication) for the detection of replication stress and specified imaging outcomes (mid line is mean+/− standard deviation, n = 100), highlighting the re-establishment of normal replication when M6620 is added to topotecan in the SCLC cell model DMS114. C) Cell viability with SN-38 and M6620 across different treatment schedules in the SCLC cell line H446. M6620 followed by SN-38 does not yield a synergistic effect on cell viability, SN-38 followed by M6620 and co-administration of both drugs creates a synergistic effect. Group I: M6620 for 24 hours followed by 24 hours of SN-38; Group II: concurrent M6620 and SN-38 (24 hours); Group III: concurrent M6620 and SN-38 (24 hours) followed by an additional 24 hours of M6620; Group IV: SN-38 for 24 hours followed by 24 hours of M6620. D) In vivo assessment (mean tumor volume +/− standard deviation, n = 5) of irinotecan (50 mg/kg, IP) alone and combination of irinotecan (50 mg/kg, IP) and M6620 (20 mg/kg, IV) in SCLC PDX LXFS573 model using a 3-cycle schedule with treatments on days 1, 8 and 15. Vertical dashed line marks end of third treatment cycle after 21-days. See also Table S2, Fig. S2.