Primary central nervous system lymphoma (PCNSL) is the second most common cause of focal CNS disease in AIDS patients, for whom it is typically fatal within 4-6 weeks. AIDS-related PCNSL is almost universally associated with EBV and effective therapy does not exist. Recognition of a continuing contribution by EBV to the growth phenotype of some EBV-linked tumors re-emphasizes the validity of EBV as therapeutic target. Based on in vitro studies, in which non-cytotoxic levels of the ribonucleotide reductase inhibitor hydroxyurea (HU) induced loss of EBV episomes from lymphoblastoid cell lines and Burkitt's lymphoma-derived cell lines, we investigated the anti-tumor efficacy of this drug in vivo. Two patients, aged 13 and 37 years, with PCNSL as the presenting feature of advanced HIV-1 infection were treated with oral, low dose HU (400-700 mg/m2/ day). Both patients had severe neurologic impairment as a consequence of the tumor. In response to initiation of anti-retroviral therapy (HAART), neither patient developed a sustained increase in their CD4+ cell count and the HIV-1 burden in their peripheral blood remained relatively high. However, both patients showed striking clinical, neurologic and radiologie improvement of PCNSL while on HU therapy, with responses persisting at 23 and 25 months to date. The absence of immune recovery on HAART and the noncytotoxic doses of HU administered suggest that HU-mediated tumor regression was based on an anti-EBV effect. These findings suggest the promise of EBV-targeted therapeutic strategies for other select malignant diseases. The safe therapeutic profile of low-dose HU, the convenience of an oral outpatient regimen, and the durable responses provide the impetus for more extensive trials of hydroxyurea in AIDS related PCNSL.
|Original language||English (US)|
|Issue number||11 PART I|
|Publication status||Published - Dec 1 2000|
All Science Journal Classification (ASJC) codes
- Cell Biology