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Biological properties of IDN5174, a new synthetic camptothecin with the open lactone ring.
Cancer Res. 2006 Nov 15; 66(22):10976-82.CR

Abstract

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.

Authors+Show Affiliations

Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17108136

Citation

Beretta, Giovanni L., et al. "Biological Properties of IDN5174, a New Synthetic Camptothecin With the Open Lactone Ring." Cancer Research, vol. 66, no. 22, 2006, pp. 10976-82.
Beretta GL, Petrangolini G, De Cesare M, et al. Biological properties of IDN5174, a new synthetic camptothecin with the open lactone ring. Cancer Res. 2006;66(22):10976-82.
Beretta, G. L., Petrangolini, G., De Cesare, M., Pratesi, G., Perego, P., Tinelli, S., Tortoreto, M., Zucchetti, M., Frapolli, R., Bello, E., Manzotti, C., Fontana, G., Bombardelli, E., Battaglia, A., Samorì, C., & Zunino, F. (2006). Biological properties of IDN5174, a new synthetic camptothecin with the open lactone ring. Cancer Research, 66(22), 10976-82.
Beretta GL, et al. Biological Properties of IDN5174, a New Synthetic Camptothecin With the Open Lactone Ring. Cancer Res. 2006 Nov 15;66(22):10976-82. PubMed PMID: 17108136.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biological properties of IDN5174, a new synthetic camptothecin with the open lactone ring. AU - Beretta,Giovanni L, AU - Petrangolini,Giovanna, AU - De Cesare,Michelandrea, AU - Pratesi,Graziella, AU - Perego,Paola, AU - Tinelli,Stella, AU - Tortoreto,Monica, AU - Zucchetti,Massimo, AU - Frapolli,Roberta, AU - Bello,Ezia, AU - Manzotti,Carla, AU - Fontana,Gabriele, AU - Bombardelli,Ezio, AU - Battaglia,Arturo, AU - Samorì,Cristian, AU - Zunino,Franco, PY - 2006/11/17/pubmed PY - 2006/12/15/medline PY - 2006/11/17/entrez SP - 10976 EP - 82 JF - Cancer research JO - Cancer Res. VL - 66 IS - 22 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/17108136/Biological_properties_of_IDN5174_a_new_synthetic_camptothecin_with_the_open_lactone_ring_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17108136 DB - PRIME DP - Unbound Medicine ER -