TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer.

We have explored a unique combination therapy for metastatic colorectal cancer. This strategy combines a potent and new oncolytic poxvirus expressing a membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or TNFSF10) and oxaliplatin (Ox) chemotherapy. We hypothesized that TRAIL expression would increase the efficacy of the oncolytic poxvirus, and that the therapeutic efficacy would be further enhanced by combination with chemotherapy. The cytotoxicity to cancer cells by Ox, oncolytic vaccinia virus (VV) and trail gene-armed VV alone or in combination was tested in vitro. The trail gene armed oncolytic VV-expressed high levels of TRAIL in infected cancer cells and had greater potency as a cytotoxic agent compared with the parent VV. Ox alone exerted concentration-dependent cytotoxicity. In vitro, the combination of the two agents applied at suboptimal concentrations for individual therapy displayed synergy in inducing cancer cells into enhanced levels of apoptosis/necrosis. Western blot analyses were consistent with the notion that TRAIL induced cancer cell death mainly through apoptosis, whereas Ox and vJS6 induced cell death more through non-apoptotic death pathways. In two aggressive colorectal carcinomatosis models derived from human HCT116 and murine MC38 cells, the combination therapy displayed synergistic or additive antitumor activity and prolonged the survival of the tumor-bearing mice compared with either Ox chemotherapy or vvTRAIL-mediated oncolytic gene therapy alone. This combination strategy may provide a new avenue to treating peritoneal carcinomatosis and other types of metastases of colorectal cancer.

Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway.

Despite adequately expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, malignant cells are frequently refractory to the cytotoxic effect of this apoptosis-inducing ligand. The susceptibility of cancer cells to TRAIL can be potentiated by cisplatin (CDDP). This study was designed to evaluate the ability of cisplatin to enhance the cytotoxic effect of TRAIL gene therapy using the recombinant adenovirus-mediated tumor-selective expression of membrane-bound green fluorescence protein (GFP)-TRAIL fusion protein (AdVgTRAIL) on thoracic cancer cells and to elucidate the putative mechanisms responsible for this synergistic combination effect. While causing little death of cultured thoracic cancer cells by itself, AdVgTRAIL in combination with CDDP, on the other hand, mediated profound supra-additive cytotoxicity and apoptosis via a strong bystander effect. CDDP/AdVgTRAIL-induced cytotoxicity was completely abrogated either by the pancaspase inhibitor zVAD-fmk or by the selective caspase 9 inhibitor or by transient knockdown of caspase 9 by siRNA, indicating that this process was caspase-mediated and mitochondria-dependent. This was confirmed by the observation that Bcl2 overexpression protected the cells from combination-induced cytotoxicity. Robust activation of caspase 8 activity in combination-treated cells was blocked by overexpression of Bcl2, indicating that caspase 8 activation was secondary to the mitochondria-mediated amplification feedback loop. Combining CDDP with AdVgTRAIL greatly enhances its tumoricidal efficacy in cultured thoracic cancer cells in vitro. The two agents interact to mediate profound activation of caspase cascade via recruitment of the mitochondria and positive feedback loop. The CDDP/AdVgTRAIL combination also exhibits a strong antitumor effect in in vivo animal model of human cancer xenografts.

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01.

Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-kappaB inhibitor) abrogates HDACI-induced transcriptional activation of NF-kappaB and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62-10.0 mM) resulted in significant cell line- and dose-dependent growth inhibition (IC(50) values: 4.1-6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5-20-fold upregulation of transcriptional activity of NF-kappaB was substantially (50-90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (<20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60-90% of cells underwent apoptosis following exposure to combinations of VA+kinase inhibitors. Kinase inhibitor-mediated suppression of NF-kappaB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kappaB by Parthenolide drastically synergised with VA to induce apoptosis (VA+Parthenolide: 60-90% compared to <20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-kappaB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kappaB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.

Jejunal diverticulosis and gastrointestinal bleeding.

Occult gastrointestinal bleeding frequently frustrates clinicians' attempts to locate the source. Foci of hemorrhage within the small bowel are often found only at laparotomy and can be attributed to Meckel's diverticula, carcinomas, or less frequently, pulsion-type diverticula. We report our experience with two patients whose jejunal diverticula resulted in recurrent episodes of massive gastrointestinal hemorrhage.

Carcinosarcoma of the esophagus--pattern of recurrence.

Carcinosarcoma of the esophagus is a rare malignant neoplasm, predominantly affecting men in their seventh decade of life. While presenting symptoms and anatomic location of squamous cell and carcinosarcoma of the esophagus are similar, the latter often presents as a large intraluminal polypoid mass on barium esophagram. The more favorable prognosis associated with carcinosarcoma versus other esophageal neoplasms has been attributed to early onset of symptoms, resulting in prompt diagnosis, and a lower propensity for tumor invasion. We report the case of an elderly woman presenting with dysphagia who was initially diagnosed with esophageal leyomyosarcoma. Final tumor pathology showed esophageal carcinosarcoma.