Age-Related Differences in Vincristine Toxicity and Biodistribution in Wild-Type and Transporter-Deficient Mice
| Autor: | Toshinari Muramatsu, Linda K Johnson, Rick Avery Finch, Alan C. Sartorelli, Z. Ping Lin, Giuseppe Pizzorno, Janine J. Leffert, Dennis R. Johnson |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Cancer Research Vincristine medicine.medical_specialty Genotype Ratón medicine.drug_class Weanling Pharmacology Vinca alkaloid Mice Equivalent Internal medicine medicine Animals P-glycoprotein biology Reverse Transcriptase Polymerase Chain Reaction Age Factors Wild type General Medicine Antineoplastic Agents Phytogenic Endocrinology Oncology Toxicity biology.protein ATP-Binding Cassette Transporters Female Genes MDR medicine.drug |
| Zdroj: | Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics. 14:331-343 |
| ISSN: | 0965-0407 |
| Popis: | The impact of mouse multidrug resistance genes mdrla/b and mrpl on age-related differences in the toxicity and biodistribution of vincristine (VCR) was evaluated in wild-type, mrpl(-/-), mdrla/b(-/-), and combined mdrla/b(-/-), mrpl(-/-) weanling and adult mice given a single IP dose of VCR ranging from 0.0625 to 6 mg/kg. Weanling mice of all four genotypes were more sensitive than adult animals as determined by survival rate, average time of death, and pathologic findings. Wild-type animals were the least sensitive and combined mdrla/b(-/-), mrpl(-/-) mice the most sensitive to VCR toxicity. Mdrla/b(-/-) and mrpl(-/-) genotypes exhibited intermediate sensitivities, with mdrla/b(-/-) mice being more sensitive than mrpl(-/-) animals to the vinca alkaloid. Administration of [3H]VCR to wild-type and mdrla/b(-/-), mrpl(-/-) animals revealed relatively greater accumulation of radioactive VCR equivalents in weanlings over adults in several tissues, with weanling mdrla/b(-/-), mrpl(-/-) lung and heart exhibiting the greatest enhanced accumulation of 26- and 15-fold over adults, respectively. A similar cardiopulmonary differential accumulation of VCR was not observed in wild-type weanlings to adults. Semiquantitative RT-PCR expression analyses of ABC transporter genes in weanling and adult tissues of wild-type and combined mdrla/b(-/-), mrpl(-/-) mice did not reveal major age-related differences in these ABC transporters that would explain the relatively greater toxicity observed in weanling mice. However, the greater cardiopulmonary accumulation of VCR equivalents seen in the combined mdrla/b(-/-), mrpl(-/-) weanlings over that of adults underscores the potential for unique organ and age-related toxicities of this agent in the setting of transporter deficiency. |
| Databáze: | OpenAIRE |
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