Anticancer drug toxicity via cytokine production: the hydroxyurea paradigm

Our previous observations on the toxic effects of hydroxyurea (HU) in adrenalectomized (ADX) rats prompted us to suggest that these effects might be mediated by an increased synthesis of proinflammatory cytokines. This study was conducted to determine whether HU stimulates cytokine gene expression in vivo. The polymerase chain reaction (PCR) technique was used to assess levels of mRNA for interleukin-1 alpha (IL-1 alpha), tumor necrosis factor (TNF) and interleukin-4 (IL-4) in spleen cells from intact and ADX rats treated with HU or vehicle. In ADX rats, expression of proinflammatory-cytokine mRNA was markedly increased by HU, but no expression of these genes was seen in intact animals after treatment. In the latter rats, cytokine-gene expression seemed to be down-regulated by HU-induced elevations in plasma corticosterone levels, since IL-1 alpha and TNF transcripts could be detected only after corticosterone levels had returned to normal (24 h after treatment). Interestingly, IL-4 mRNA could not be detected in either treated or untreated ADX rats, indicating that expression of this gene is closely related to circulating levels of corticosterone. These findings strongly suggest that the increased toxicity displayed by HU in ADX animals is mediated by stimulation of cytokine synthesis in vivo.