Complete Regression of Xenografted Human Carcinomas by Camptothecin Analogue-Carboxymethyl Dextran Conjugate (T-0128)
2000
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 M r
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.
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