Preclinical efficacy of i.v.
IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a
cyclodextrin-based
polymer, was investigated in several mouse xenografts. The effects of different multiple dosing schedules on
tumor growth of LS174T colon
carcinoma xenografts are elucidated. All multiple dosing schedules administered over 15 to 19 days resulted in enhanced efficacy compared with untreated or single-dose groups. Further improvements in antitumor efficacy were not observed when the dosing frequency was increased from three weekly doses to five doses at 4-day intervals or 5 days of daily dosing followed by 2 days without dosing repeated in three cycles using similar cumulative doses. This observation was attributed to the extended release characteristics of
camptothecin from the
polymer. Antitumor efficacy was further evaluated in mice bearing six different s.c. xenografts (LS174T and HT29
colorectal cancer, H1299
non-small-cell lung cancer, H69
small-cell lung cancer, Panc-1
pancreatic cancer, and MDA-MB-231
breast cancer) and one disseminated xenograft (TC71-luc
Ewing's sarcoma). In all cases, a single treatment cycle of three weekly doses of
IT-101 resulted in a significant antitumor effect. Complete
tumor regression was observed in all animals bearing H1299
tumors and in the majority of animals with disseminated
Ewing's sarcoma tumors. Importantly,
IT-101 is effective in a number of
tumors that are resistant to treatment with
irinotecan (MDA-MB-231, Panc-1, and HT29), consistent with the hypothesis that polymeric
drug conjugates may be able to overcome certain kinds of multidrug resistance. Taken together, these results indicate that
IT-101 has good tolerability and antitumor activity against a wide range of
tumors.