MEN4901/T-0128, a new camptothecin derivative-carboxymethyldextran conjugate, has potent antitumor activities in a panel of human tumor xenografts in nude mice.

Abstract

PURPOSE:

The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513.

EXPERIMENTAL DESIGN:

We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4.

RESULTS:

MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo.

CONCLUSIONS:

Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

• Authors: Fumiko Fujita, Masako Koike, Masahide Fujita, Yasuo Sakamoto, Satoshi Okuno, Takayuki Kawaguchi, Shigeru Yano, Toshiro Yano, Satoko Kiuchi, Toshihisa Fujiwara, Shinzoh Kudoh, Masatoshi Kakushima
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 4 Pg. 1650-7 (Feb 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15746070 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents
• Dextrans
• Irinotecan
• Topotecan
• T 0128
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Area Under Curve
• Body Weight (drug effects)
• Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Dextrans (chemistry, pharmacokinetics, pharmacology)
• Humans
• Irinotecan
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Time Factors
• Topotecan (analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
• Treatment Outcome
• Xenograft Model Antitumor Assays (methods)