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 day 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 to irinotecan-treated and untreated mice. At the most efficacious dose of MEN4901/T-0128, only 1 of 12 animals had lymph node metastasis compared to 19 of 24 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.

Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development

“…This model is generated faster than the former model. In the hybrid of the ectopic and orthotopic models, fluorescence-expressing HT- 29 cells (human colon cancer) are subcutaneously injected into the ectopic site and several pieces of HT-29 cellderived tumors are transplanted into the colon, and then metastasis is observed (24) . Generally, a metastasis model is more easily obtained in SCID mice than in nude mice.…”

“…Generally, a metastasis model is more easily obtained in SCID mice than in nude mice. Because metastasis, as in the orthotopic model, is difficult to observe in appearance except in the case of skin cancer (25) , genetically engineered cell lines (fluorescence (24) or luciferase-expressing cells (26) ) were utilized and monitored using in vivo optical imaging. Frequently, this model is applied for theragnosis, which involves imaging by MRI or positron emission tomography (PET) (27) to simultaneously diagnose and determine the appropriate anti-cancer therapy.…”

Adjuvant treatment with tumor-targetingSalmonella typhimuriumA1-R reduces recurrence and increases survival after liver metastasis resection in an orthotopic nude mouse model

“…The human colon cancer cell line HT-29, [ 52 , 53 ] was maintained in DMEM (Irvine Scientific, Irvine, CA) supplemented with heat-inactivated 10% fetal bovine serum (FBS) (Gemini Biologic Products, Calabasas, CA), 2 mM glutamine, 100 units/ml penicillin, 100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B (Life Technologies, Inc., Grand Island, NY). The cells were incubated at 37°C in 5% CO2.…”

Therapeutic efficacy of tumor-targetingSalmonella typhimuriumA1-R on human colorectal cancer liver metastasis in orthotopic nude-mouse models

“…The human colon cancer cell line HT-29 [ 55 , 56 ] was maintained in DMEM (Irvine Scientific, Irvine, CA) supplemented with heat-inactivated 10% fetal bovine serum (FBS) (Gemini Biologic Products, Calabasas, CA), 2 mM glutamine, 100 units/ml penicillin, 100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B (Life Technologies, Inc., Grand Island, NY). The cells were incubated at 37°C in 5% CO 2 .…”