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In-vivo identification of tumor multidrug resistance with 3H-colchicine [corrected]
B M Mehta1, E Rosa, J D Fissekis
1Nuclear Medicine Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 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 microgram/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 less than 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 less than 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.
Insights
Detecting multidrug resistance (MDR) in cancer is key. Researchers used radiolabeled colchicine ([3H]-CHC) in mice to show that resistant tumors take up less of the drug, enabling in vivo identification of MDR.
Area of Science:
- Oncology
- Pharmacology
- Radiochemistry
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy, particularly with natural product agents.
- Early in vivo identification of MDR is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the in vivo distribution of radiolabeled colchicine ([3H]-CHC) in tumors with varying sensitivities to colchicine.
- To establish a foundation for developing radiolabeled drugs for detecting MDR in cancer patients.
Main Methods:
- Radiolabeled [3H]-colchicine ([3H]-CHC) was administered to immunosuppressed mice bearing xenografts of colchicine-sensitive and resistant tumor cell lines.
- In vivo distribution of radioactivity was measured at trace and LD50 dose levels.
- Chromatographic analysis was used to assess the metabolic fate of [3H]-CHC in plasma and tumor tissues.
Main Results:
- Activity concentration was significantly higher in sensitive tumors compared to resistant tumors (p < 0.01) at 60 minutes post-injection.
- No significant difference in activity distribution was observed between trace and high-dose injections.
- Metabolic degradation of [3H]-CHC occurred extensively in plasma and tumors, with protein-bound [3H]-CHC contributing to the higher concentration in sensitive tumors (3:1 ratio, p < 0.05).
Conclusions:
- This study demonstrates the feasibility of distinguishing multidrug-resistant from sensitive tumors in vivo using radiolabeled MDR drugs.
- The findings suggest that [11C]-colchicine could serve as a radiopharmaceutical for quantitative PET imaging of MDR in human tumors.