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In-Vivo Identification of Tumor Multidrug Resistance with Tritium-3-Colchicine

Nuclear Medicine Research Laboratory and Laboratory of Cellular and Biochemical Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York

Correspondence: For reprints contact: Bipin M. Mehta, Ph D, Nuclear Medicine Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

ABSTRACT

Multidrug resistance (MDR) is a major obstacle in the clinical treatment of cancer with natural-product anticancer agents. Identification of MDR in vivo could be important in the design of chemotherapeutic regimens. As a first step in developing radiolabeled drugs to detect MDR, we measured the in vivo distribution of radiolabel from [ring C, methoxy-³H]-colchicine ([³H]-CHC) in immunosuppressed mice bearing xenografts of colchicine-resistant and sensitive tumor cell lines. Experiments were done at trace (1 µg/kg) and LD₅₀ (4 mg/kg) dose levels. Activity concentration/injected dose was more than twice as great in sensitive as in resistant tumors (p < 0.01) at 60 min following retroorbital injection of [³H]-CHC. There was no significant difference in activity distribution between trace- and high-dose injections for any of the tissues sampled. Chromatographic analysis of plasma and tumor extracts demonstrated extensive extravascular metabolic degradation of [³H]-CHC. The ratio of [³H]-CHC concentration of injected dose between sensitive and resistant tumors was 3:1 (p < 0.05), due primarily to protein-bound [³H]-CHC. This preliminary study demonstrates that it is possible to distinguish multidrug resistant from sensitive tumors in vivo on the basis of radiolabel uptake from an injected MDR drug. Colchicine, labeled with ¹¹C at the [ring C]-methoxy group, may be useful as a radiopharmaceutical for quantitative identification of MDR in human tumors using PET.

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