Open AccessAge-Related Differences in Vincristine Toxicity and Biodistribution in Wild-Type and Transporter-Deficient Mice
Author(s) -
Toshiya Muramatsu,
Dennis R. Johnson,
Robert A. Finch,
Linda K. Johnson,
Janine J. Leffert,
ZhenYuan Lin,
Giuseppe Pizzorno,
Alan C. Sartorelli
Publication year - 2004
Publication title -
oncology research
Language(s) - English
Resource type - Journals
eISSN - 1555-3906
pISSN - 0965-0407
DOI - 10.3727/0965040041292387
Subject(s) - weanling , toxicity , vincristine , biology , vinca alkaloid , wild type , medicine , pharmacology , endocrinology , mutant , chemotherapy , gene , biochemistry , cyclophosphamide
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.