In a recent issue of AIDS Hoffmann et al.  reported dramatically improved survival rates for AIDS patients suffering from primary central nervous system lymphoma (PCNSL) treated with highly active antiretroviral therapy (HAART) and cranial irradiation . In this retrospective analysis the authors showed excellent results of combined treatment (HAART plus cranial irradiation) when compared with cranial irradiation treatment alone or no cancer-specific treatment. The authors concluded that HAART leads to a dramatic improvement of survival in these patients by enhancing immunity. Given that an impaired immune system gives rise to this tumour entity, it is tempting to assume that an enhanced immune system might grant remission from PCNSL in patients in whom the tumour burden is severely reduced by radiation therapy. However, in the multivariate analysis the CD4 cell counts failed to predict outcome, whereas cranial irradiation and HAART were independent variables for survival.
An alternative explanation is that HAART may radiosensitize to cranial irradiation. Part of the HAART protocol involves the use of protease inhibitors initially designed to target only the HIV-1 protease . However, recent studies from our laboratory and another laboratory showed that the HIV-1 protease inhibitors ritonavir  and saquinavir (Pajonk et al., submitted for publication) have inhibitory effects on the 26s multi-catalytic protease called the proteasome . Protease activity is increased in malignant cells , the subcellular distribution of proteasomes changes during the cell cycle , and tumour cells show a different pattern of proteasome sub-unit expression , making the proteasome a target for cancer therapy that might be exploited with therapeutic benefit . We and other authors have already shown that the inhibition of this protease using specific inhibitors such as MG-132 or PS-341 induces apoptosis in human tumour cells [9,10]. In addition, short-time inhibition in vitro at concentrations sub-optimal to kill tumour cells in vivo sensitized malignant cells to ionizing radiation [10,11]. Recent studies from our laboratory revealed comparable effects for saquinavir on human prostate cancer and glioma cell lines (Pajonk et al., submitted for publication). This offers an entirely new explanation for the promising results of Hoffmann and colleagues , identifying HIV-1 protease inhibitors as radiosensitizing agents in patients with HIV-related PCNSL. It may be possible to re-analyse the data from this study for the use of HIV-1 protease inhibitors. If the patients with prolonged survival received HIV-1 protease inhibitors, a prospective clinical trial testing HIV-1 protease inhibitors containing HAART regimens versus HAART regimens without these inhibitors, both combined with cranial irradiation, should be considered. Given the expectation of increased radiation neurotoxicity, which was also indicated in the data from Hoffman et al. , a dose escalation trial may be needed to maximize the therapeutic benefit to be derived from this combined modality treatment. It is worth noting that better responses have been noted to chemotherapy in AIDS patients with non-Hodgkin's lymphoma who receive concurrent HAART , possibly because of the same mechanism.
William H. McBrideb
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