BMC Cancer 2009, 9:372 http://www.biomedcentral.com/1471-2407/9/372 TFuigmuorre g2rowth during Sulfasalazine treatment Tumor growth during Sulfasalazine treatment. A/Tumor growth between inclusion and sulfasalazine treatment arrest (volumes are provided in ml and were measured by segmentation on gadolinium-enhanced T1 MRI scans); B/Gadolinium- enhanced T1 MRI scans of patient #05 at the time of inclusion and after 32 days of sulfasalzine treatment (6 g/day). The tumor volume has more than tripled over this period. tors might contribute to this discrepancy. First, the small number and large tumor burden of the patients analyzed in this study may have missed or masked a limited drug efficacy. Second, of the 8 tumors for which MGMT pro- moter analysis could be performed, 7 (87.5%) were unmethylated, a known factor of overall tumor resistance against alkylating agent therapy [30]. Third, the overall pharmacokinetics of sulfasalazine might differ between mice and humans, and different routes of administration were used in preclinical and clinical experiments (intra- peritoneal injection in mice, oral use in humans). Fourth, Sulfasalazine targets only one of several pathways to NF- kappaB activation, which may result in malignant gliomas escaping treatment effect by utilizing accessory NF-kap- paB pathways. Interestingly, an immunohistochemistry to p65 was performed on the tumor of the patient who was re-operated after sulfasalazine cessation, and showed abundant cytoplasmic and nuclear NF-kappaB reactivity. These highly resistant and heterogeneous tumors could thus rapidly develop mechanisms of resistance to sul- fasalazine and/or IKK-independent routes of NF-kappaB activation. Accordingly, PFS during sulfasalazine treat- ment remained marginal. In addition, differences in NF- kappaB-related pathways may exist between malignant glioma cell lines, primary cultures of malignant glioma, and malignant gliomas specimens [31]. Fifth, Sulfasala- Page 5 of 8 (page number not for citation purposes)