12,13-Dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c] pyrimido[5,6,1-jk] carbazole-4,6,10(5H,11H)-trione hydrochloride (ER-37328) is a novel
topoisomerase II poison with potent tumoricidal activity against solid
tumor cells both in vitro and in vivo. Here, we describe studies on the effects of
ER-37328 on the primary
tumor, liver
metastasis, and survival in a murine Colon 38 orthotopic
transplantation model. When
ER-37328 (10 mg/kg) was administered i.v. at 11 days or 20 days after
transplantation, strong regression of the primary
tumor was observed on both administration schedules. On the later schedule,
ER-37328 completely blocked liver
metastasis, whereas the mean number of
metastases in the control group was 23.9. To examine the antitumor activity against Colon 38 at the liver in more detail,
ER-37328 was administered to mice that had received an inoculation of Colon 38
tumor into the liver.
ER-37328 showed strong
tumor-regression activity against Colon 38 growing in the liver. In addition, administration of
ER-37328 on a schedule of every 7 days four times caused a significant increase of 79% in life span in the orthotopic
transplantation model, calculated by using mean survival times. Pharmacokinetic study revealed that
ER-37328 was highly distributed to the
tumor and organs. The ratios of the area under the concentration-time curves of
ER-37328 in the
tumor, lung, liver, and kidney versus plasma were 81, 77, 47, and 40, respectively. This high distribution to the
tumor and liver may explain the potent antitumor activity of
ER-37328 against Colon 38
tumor in the liver. In conclusion, the
topoisomerase II poison ER-37328 is a promising candidate for clinical application against
colon cancer.