High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate.

Abstract

The antimetastatic activity of a novel camptothecan conjugate, MEN4901/T-0128, in which 7-ethyl-10-aminopropyloxy-camptothecin (T-2513) is bound to a biodegradable carboxymethyldextran via a Gly-Gly-Gly linker, was observed in this study. High antimetastatic activity of MEN4901/T-0128 was demonstrated in a clinically-relevant orthotopic mouse model of human colon cancer. MEN4901/T-0128 and irinotecan were compared for anti-metastatic activity as well as efficacy against the primary tumor. An imageable, metastatic model was made by surgical orthotopic implantation (SOI) of the green fluorescent protein (GFP)-expressing HT-29 tumor in nude mice. MEN4901/T-0128 and irinotecan were administered intravenously at various doses and schedules. MEN4901/T-0128, with treatment beginning on d 49 after SOI, was highly effective on lymph node metastasis as well as against the primary tumor. Both GFP imaging and histology demonstrated a markedly lower metastatic incidence of lymph nodes in all MEN4901/T-0128 treated mice compared with irinotecan-treated and untreated mice. At the most efficacious dose of MEN4901/T-0128, only 1 of 12 animals had lymph node metastasis compared with 19 of 20 in the control group. The present study demonstrates the principle that when a camptothecan is conjugated to an appropriate polymer, the drug can become extremely effective with important clinical potential for antimetastatic therapy, a most urgent need.

• Authors: Huaiyu Ma, Xiaoming Li, Zhijian Yang, Satoshi Okuno, Takayuki Kawaguchi, Shigeo Yagi, Michael Bouvet, Robert M Hoffman
• Journal: The Journal of surgical research (J Surg Res) Vol. 171 Issue 2 Pg. 684-90 (Dec 2011) ISSN: 1095-8673 [Electronic] United States
• PMID: 20851421 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Dextrans
• Prodrugs
• Green Fluorescent Proteins
• Irinotecan
• Topotecan
• carboxymethyl dextran
• T 0128
• Camptothecin

Topics

• Adenocarcinoma (drug therapy, secondary)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Body Weight (drug effects)
• Camptothecin (analogs & derivatives, pharmacology)
• Colonic Neoplasms (drug therapy, pathology)
• Dextrans (pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Green Fluorescent Proteins (genetics)
• HT29 Cells
• Humans
• Irinotecan
• Mice
• Mice, Nude
• Prodrugs (pharmacology)
• Topotecan (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays