A series of water-soluble camptothecins obtained by linking a
spermidine moiety to the 21-position of the open form through an amidic bond have been tested for their biochemical and biological activities. Growth inhibition assay on the human
non-small cell lung cancer carcinoma NCI-H460 cell line revealed that the
camptothecin analogues were less potent than
topotecan and SN38 after 1 hour of treatment. The potency increased after 72 hours of exposure, being similar to that of reference camptothecins. The analysis of
topoisomerase I-mediated DNA cleavage using the purified
enzyme indicated that the novel
camptothecin analogues retained ability to
poison topoisomerase I and displayed the same cleavage pattern of SN38. Persistence of the DNA cleavage was comparable with that of SN38. Stabilization of the cleavable complex was not the result of hydrolysis of the N-C bond between
polyamine and the drug because no free
camptothecin was recovered at the end of DNA cleavage in presence of
IDN5174, the analogue selected for detailed studies.
IDN5174 exhibited an antitumor activity comparable with that of
topotecan and
irinotecan against NCI-H460
tumor xenograft. The pharmacokinetics in mice showed a favorable disposition in
tumor tissue with low amount of
camptothecin detectable in plasma and
tumor (around 5-10%), thus supporting the efficacy of intact
IDN5174. In conclusion, we found that
IDN5174 maintained the biological and antitumor properties, in spite of lack of the closed E ring. The available results support the interpretation that the
polyamine linked at the 21-position may allow a favorable drug interaction in the ternary complex.