title: 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.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okuno
authors.forename: M
authors.initials: M
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Yano
authors.forename: S
authors.initials: S
authors.lastname: Yano
authors.forename: S
authors.initials: S
authors.lastname: Kiuchi
authors.forename: N
authors.initials: N
authors.lastname: Tsuda
authors.forename: Y
authors.initials: Y
authors.lastname: Sakamura
authors.forename: J
authors.initials: J
authors.lastname: Imai
authors.forename: T
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: K
authors.initials: K
authors.lastname: Tsujihara
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002453:Cell Cycle / Q000187:drug effects; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution; D019772:Topotecan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D003911:Dextrans; D011355:Prodrugs; C410030:T 2153; D019772:Topotecan; C410031:T 0128; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin