Survival of AIDS patients with primary central nervous system lymphoma may be improved by the radiosensitizing effects of highly active antiretroviral therapy
Pajonk, Franka; McBride, William H.b
aDepartment of Radiation Oncology, Molecular Radiation Biology Laboratory, University Clinic Freiburg, Freiburg, Germany; and bDepartment of Radiation Oncology, Experimental Division, UCLA School of Medicine, Los Angeles, CA, USA.
Received: 11 January 2002; accepted: 15 January 2002.
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
1. Hoffmann C, Tabrizian S, Wolf E. et al
. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 2001, 15: 2119–2127.
2. Flexner C. HIV-protease inhibitors. N Engl J Med 1998, 338: 1281–1292.
3. Schmidtke G, Holzhutter HG, Bogyo M. et al
. How an inhibitor of the HIV-I protease modulates proteasome activity. J Biol Chem 1999, 274: 35734–35740.
4. Ciechanover A. The ubiquitin–proteasome proteolytic pathway. Cell 1994, 79: 13–21.
5. Kumatori A, Tanaka K, Inamura N. et al
. Abnormally high expression of proteasomes in human leukemic cells. Proc Natl Acad Sci U S A 1990, 87: 7071–7075.
6. Amsterdam A, Pitzer F, Baumeister W. Changes in intracellular localization of proteasomes in immortalized ovarian granulosa cells during mitosis associated with a role in cell cycle control. Proc Natl Acad Sci USA 1993, 90: 99–103.
7. Kanayama H, Tanaka K, Aki M. et al
. Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells. Cancer Res 1991, 51: 6677–6685.
8. Adams J, Palombella VJ, Elliott PJ. Proteasome inhibition: a new strategy in cancer treatment. Invest New Drugs 2000, 18: 109–121.
9. Drexler HC. Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad Sci USA 1997, 94: 855–860.
10. Pajonk F, Pajonk K, McBride W. Apoptosis and radisensitization of Hodgkin's cells by proteasome inhibition. Int J Radiat Oncol Biol 2000, 47: 1025–1032.
11. Pervan M, Pajonk F, Sun JR, Withers HR, McBride WH. Molecular pathways that modify tumor radiation response. Am J Clin Oncol 2001, 24: 481–485.
12. Antinori A, Cingolani A, Alba L. et al
. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 2001, 15: 1483–1491.
This article has been cited 7 time(s).
Blood ReviewsImmunodeficiency-associated lymphomasBlood Reviews
International Journal of Radiation Oncology Biology PhysicsCurrent Management of Primary Central Nervous System LymphomaInternational Journal of Radiation Oncology Biology Physics
NeurosurgeryUtility of brain biopsy in patients with acquired immunodeficiency syndrome before and after introduction of highly active antiretroviral therapyNeurosurgery
Failla Memorial Lecture - A sense of danger from radiation
Radiation Research, 162(1):
Hematology-Oncology Clinics of North AmericaAIDS-related primary central nervous system lymphomaHematology-Oncology Clinics of North America
OncogeneThe role of the ubiquitin/proteasome system in cellular responses to radiationOncogene
Current Opinion in NeurologyPrimary central nervous system lymphomasCurrent Opinion in Neurology
© 2002 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.