Cell Cycle–Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation

Abstract

The antineoplastic drug sorafenib ) is a multikinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G 2 -M. In synchronized cells, sorafenib causes a reversible G 1 delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies. [Cancer Res 2007;67(19):9443-54]

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells

“…ketamine/xylazine), followed by detection of live images using the Xenogen IVIS at 15 min postinjection. Regions of interest were drawn over the tumor areas as previously described (13,14). Bioluminescence signal was recorded as maximum (photons/s/cm 2 /steridian).…”

“…on days 17 and 19, respectively. To use tumor bioluminescence to quantify relative xenograft growth (14), the mice were imaged using the Xenogen IVIS system on days 14 (pretherapy) and 24 (posttherapy) to determine p/s/cm 2 /steridian. As shown in Fig.…”

Sorafenib combined with cryoablation to treat unresectable hepatocellular carcinoma

“…Most patients enrolled in our study had poor overall prognosis because of worsening underlying cirrhosis (Child-Pugh class B) or in infiltrating, far-advanced HCC. A recent phase 2 open-label study of single agent sorafenib in treating advanced HCC with similar study populations like us showed 8% response rate and 18% disease-stabilization rate [17] . The higher disease-stabilization rate and DCR rate observed in our study may be contributed to the necrosis induced by cryoablation and also sorafenib.…”

“…The major limitation of the current study is its nonrandomized design, and we could only compare the results with the other studies [7,17] . We didn't compare the patients who had metastasis (53.8%) with the others who had no far metastasis.…”

Efficacy and Safety of Sorafenib for Advanced Non-Small Cell Lung Cancer: a Meta-analysis of Randomized Controlled Trials

“…In the NExUS and NCCTG N0626 study, concomitant administration of sorafenib and chemotherapy may impact the efficacy of sorafenib in advanced non-small cell lung cancer (Molina et al, 2011;Paz-Ares LG et al, 2012). Sorafenib inhibits tumor growth by inducing G1 cell cycle arrest, thus potentially interfering with the cycle-dependent toxicity of chemotherapy when this is administered concomitantly (Plastaras et al, 2007;Takezawa et al, 2009;Li et al, 2013). However, the NExUS trial still showed a clinically modest but statistically significant PFS.…”