EO9: A novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models

EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, E09 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, E09 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared to leukaemia cell lines both in the Corbett two-tumour assay and in the disease-oriented human tumour cell line panel of the U.S. National Cancer Institute. In the latter system activity was particularly apparent in colon, melanoma and central nervous system lines, together with some renal and non-small cell lung lines. Preferential cytotoxicity towards hypoxic versus aerobic EMT6 mouse mammary tumour cells was observed. In vivo, EO9 was inactive against the P388 murine leukaemia, while exerting significant antiproliferative effects against several murine and human solid tumours, including the generally resistant MAC mouse colon tumours and gastric, ovarian and breast xenografts. These results confirmed in vitro observations of preferential solid tumour activity. In animal toxicology studies, E09 induced vascular congestion in the gastrointestinal tract, but no significant bone marrow toxicity. The ld₁₀ value of E09 after a single intravenous injection into mice was 9 mg/kg (27 mg/m²). A dose of one-tenth of the mouse equivalent ld₁₀ (2.7 mg/m²), the recommended starting dose for clinical phase I studies, was found to be safe in rats. Considering its distinct mechanism of bioactivation as compared to mitomycin C, its preferential solid tumour activity, its excellent activity against hypoxic cells, and lack of significant bone marrow toxicity in animal studies, E09 has been selected for clinical evaluation within the framework of the EORTC.