CPT-11 and Topotecan are two potent DNA topoisomerase I inhibitors in clinical. CPT-11 is the prodrug of SN-38. Topotecan is a water-soluble semisynthetic derivative of Camptothecin. CPT-11 is mainly for the treatment of advanced and/or metastatic colorectal cancer (CRC), whilst Topotecan is mainly for the treatment of late-stage ovarian cancer and small cell lung cancer (SCLC). However, due to some limitation of CPT-11, including BCRP, which is an ABC transporter and can efflux various anti-cancer drugs from cells, displays resistance to camptothecin agents such as SN-38 and topotecan. CPT-11 is not the better agent. Therefore, a novel topoisomerase I inhibitor, which shows superior efficacy and less individual variation than agents such as CPT-11, will be beneficial to cancer patients. In this study, CH0793076, a hexacyclic camptothecin analog, is active even against cells expressing BCRP. It inhibits DNA topoisomerase I with an IC50 of 2.3 μM.

CH-079307, an active drug and major metabolite of TP300, inhibits DNA topoisomerase I and is efficacious against cells expressing BCRP.

TP300 is stable in aqueous solutions at acidic pH levels but is rapidly converted to the active form (CH0793076) under neutral pH conditions such as in sera. TP300 did not inhibit AChE and thereby did not induce acute diarrhea at the effective dose range. Furthermore, it showed strong antitumor activity against BCRP-positive tumor xenografts and also in combination with other anti-cancer drugs.  Thus, CH-0793076 is also efficacious against cells expressing BCRP. Moreover, CH0793076 shows antiproliferative activity against PC-6/BCRP and PC-6/pRC cells, with IC50s of 0.35 and 0.18 nM, respectively. In addition, TP300 shows more than 50% of tumor growth inhibition in all nine models, regardless of the expression of BCRP (WiDr, HT-29, NCI-H460, and AsPC-1, HCT116, COLO 201, HCT-15, Calu-6 and NCI-N87).

In summary, CH-079307 is active against cells resistant to topotecan or SN-38. TP300 may have superior efficacy to CPT-11 both as a monotherapy and in combination with other drugs.


Endo M, et al. Cancer Chemother Pharmacol. 2010 Jan;65(2):363-71.