High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate.
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.
Ma
Huaiyu
H
AntiCancer, Inc., San Diego, California 92111, USA.
Li
Xiaoming
X
Yang
Zhijian
Z
Okuno
Satoshi
S
Kawaguchi
Takayuki
T
Yagi
Shigeo
S
Bouvet
Michael
M
Hoffman
Robert M
RM
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003911:Dextrans / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000494:pharmacology*; D019772:Topotecan / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D003911:Dextrans; D011355:Prodrugs; D049452:Green Fluorescent Proteins; D000077146:Irinotecan; D019772:Topotecan; C014392:carboxymethyl dextran; C410031:T 0128; D002166:Camptothecin