Complete regression of xenografted human carcinomas by camptothecin analogue-carboxymethyl dextran conjugate (T-0128).

Abstract

Clinically available camptothecins (CPTs), such as irinotecan (CPT-11) and topotecan, represent one of the most promising classes of antitumor agents, despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted T-0128, was synthesized. This prodrug is a novel CPT analogue (T-2513)-carboxymethyl (CM) dextran conjugate via a triglycine spacer, with a molecular weight of Mr 130,000. This study was designed to test the concept that the rational design of a CPT-polymer conjugate would increase the efficacy of the parent drug. The in vivo antitumor study against Walker-256 carcinoma demonstrated that T-0128 was 10 times as active as T-2513, supporting this concept. Additionally, comparative efficacy studies of T-0128, T-2513, CPT-11, and topotecan were performed using a panel of human tumor xenografts in nude mice, showing the advantage of T-0128 over these CPTs. The maximal tolerated doses (MTDs) of T-0128, T-2513, and CPT-11 were comparable. Even a single i.v. injection of T-0128 at 6 mg/kg (based on the amount of T-2513 bound to CM dextran) induced complete regression of MX-1 mammary carcinoma. T-0128 at 10 mg/kg weekly for 3 weeks (one-tenth of its MTD) cured LX-1 lung carcinoma. Also, T-0128 below its MTD consistently cured or regressed St-4 gastric and HT-29 colorectal tumor xenografts that are highly refractory to CPTs. These demonstrate the broad range of therapeutic doses achieved with T-0128. Pharmacokinetic studies were performed to correlate the efficacy results obtained for T-0128 with plasma and tissue drug concentrations using Walker-256 tumor-bearing rats. Results showed that after i.v. administration of T-0128, the conjugate continued to circulate at a high concentration for an extended period, resulting in tumor accumulation. In the tumor, the sustained release of T-2513 occurred. In contrast, T-2513 disappeared rapidly from the body. The significant increases in the amount and exposure time of released T-2513 in the tumor explain well the enhanced efficacy of T-0128. In conclusion, this study indicated that T-0128 improved the potency of T-2513, demonstrating the proof of the above concept.

• Authors: S Okuno, M Harada, T Yano, S Yano, S Kiuchi, N Tsuda, Y Sakamura, J Imai, T Kawaguchi, K Tsujihara
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 11 Pg. 2988-95 (Jun 01 2000) ISSN: 0008-5472 [Print] United States
• PMID: 10850447 (Publication Type: Journal Article)

Chemical References

• Dextrans
• Prodrugs
• T 2153
• Topotecan
• T 0128
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Animals
• Breast Neoplasms (drug therapy)
• Camptothecin (analogs & derivatives, pharmacokinetics)
• Cell Cycle (drug effects)
• Chromatography, Gel
• Chromatography, High Pressure Liquid
• DNA Topoisomerases, Type I (metabolism)
• Dextrans (chemistry, pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Female
• HeLa Cells
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prodrugs (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Wistar
• Time Factors
• Tissue Distribution
• Topotecan (analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
• Tumor Cells, Cultured