Showing papers by "Keith A. Cengel published in 2005"

Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion

Abstract: In this study, we have evaluated the interactions between ionizing radiation and a matrix metalloproteinase (MMP) inhibitor. Using Matrigel invasion assays, we show that ionizing radiation induced a dose-dependent increase in the invasive phenotype of cultured B16 melanoma cells and that conditioned medium from these irradiated B16 cells promoted endothelial cell [human microvascular endothelial cells (HMEC)] invasiveness. To determine whether the radiation-induced changes in invasive phenotype could be due to changes in MMP activation, we have tested the ability of the MMP inhibitor Metastat to modulate the ionizing radiation-induced invasive phenotype using both an in vitro melanoma model and a mouse s.c. tumor model. In these studies, Metastat inhibited the ionizing radiation-induced invasive phenotype in cultured B16 cells and similarly inhibited the increase in HMEC invasion induced by conditioned medium from irradiated B16 cells. Conversely, ionizing radiation increased B16 MMP-2 activity and the conditioned medium from irradiated B16 induced HMEC MMP-2 activity. To further investigate the interaction between ionizing radiation and MMP activation, we then studied the effects of ionizing radiation on downstream effectors of the MMP system. We found that ionizing radiation induced vascular endothelial growth factor (VEGF) secretion by B16 melanoma cells and that this secretion was inhibited by Metastat. Similarly, conditioned medium from irradiated B16 was also able to increase VEGF secretion in HMECs. Moreover, ionizing radiation-induced melanoma cell invasiveness was partially inhibited by an anti-VEGF monoclonal antibody. In vivo, ionizing radiation plus concomitant Metastat yielded the greatest growth inhibition of melanoma s.c. tumors and this effect correlated with inhibition of angiogenesis as measured by both Doppler ultrasonography and platelet/endothelial cell adhesion molecule-1 staining. Finally, ionizing radiation modulated MMP-2, VEGF, and VEGF receptor expression in these tumor samples using immunohistochemistry. Taken together, these results suggest that there is an ionizing radiation-induced tumor survival pathway and a possible paracrine ionizing radiation-induced stimulatory pathway emanating from tumor cells toward the endothelial bed that is impeded when Metastat is given simultaneously. This model could provide in vivo evidence of the antitumor efficacy of combining a MMP inhibitor with ionizing radiation to target radiation-induced invasion and angiogenesis.

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

Abstract: Activating K- ras mutations are found in ∼90% of pancreatic carcinomas and may contribute to the poor prognosis of these tumors. Because radiotherapy is frequently used in pancreatic cancer treatment, we assessed the contribution of oncogenic K- ras signaling to pancreatic cancer radiosensitivity. Seven human pancreatic carcinoma lines with activated K- ras and two cell lines with wild-type ras were used to examine clonogenic cell survival after Ras inhibition. Ras inhibition was accomplished by small interfering RNA (siRNA) knockdown of K- ras expression and by blocking Ras processing using a panel of prenyltransferase inhibitors of differing specificity for the two prenyltransferases that modify K-Ras. K- ras knockdown by siRNA or inhibition of prenyltransferase activity resulted in radiation sensitization in vitro and in vivo in tumors with oncogenic K- ras mutations. Inhibition of farnesyltransferase alone was sufficient to radiosensitize most K- ras mutant tumors, although K-Ras prenylation was not blocked. These results show that inhibition of activated K-Ras can promote radiation killing of pancreatic carcinoma in a superadditive manner. The finding that farnesyltransferase inhibition alone radiosensitizes tumors with K- ras mutations implies that a farnesyltransferase inhibitor–sensitive protein other than K-Ras may contribute to survival in the context of mutant K- ras . Farnesyltransferase inhibitors could therefore be of use as sensitizers for pancreatic carcinoma radiotherapy.

Molecular targets for altering radiosensitivity : Lessons from Ras as a pre-clinical and clinical model

Abstract: Ras activation has been correlated with malignant and metastatic cancer phenotypes and poor prognosis for cancer patients. In the preclinical setting, Ras activation by mutation or EGFR amplification results in increased clonogenic cell survival and decreased tumor growth delay following irradiation. Activation of the Ras pathway has also been associated with increased risk of local failure and decreased overall survival in patients receiving radiotherapy. Prenyltransferase inhibitors target the post-translational processing of Ras and have been shown to increase the radiosensitivity of human cancer cell lines. In the clinical setting, these inhibitors have been used with concurrent radiotherapy in a small number of phase I clinical trials with acceptable toxicity. Therefore, inhibiting Ras activation represents a promising molecular approach for radiosensitization in cancer therapy.

C225 and PDT Combination Therapy for Ovarian Cancer: The Play's the Thing

Abstract: Journal of the National Cancer Institute, Vol. 97, No. 20, October 19, 2005 The prognosis for women diagnosed with advanced-stage epithelial ovarian cancer is poor, with fewer than one-third of patients surviving 5 years. Locally advanced pelvic tumors are often associated with diffuse peritoneal carcinomatosis and bulky tumor lesions involving the omentum, bowel, mesentery, and diaphragmatic surface. Even after aggressive cytoreductive surgery and platinum-based chemotherapy, most of these patients experience local progression or recurrence. The reasons for treatment failure probably relate to diffi culties inherent to surgery within the peritoneal cavity, problems related to administering cytotoxic agents to the tumor cells in cytotoxic concentrations, and the ability of ovarian cancer cells to develop resistance to standard chemotherapies. In this issue of the Journal, del Carmen and colleagues ( 1 ) present evidence that intraperitoneal administration of C225, a humanized murine monoclonal antibody directed against the epidermal growth factor (EGF) receptor (EGFR), and benzoporphyrin derivative monoacid-A (BPD) – based photodynamic therapy (PDT) act synergistically to prevent or inhibit tumor cell growth and extend survival in a murine model of ovarian cancer peritoneal metastasis. In these studies ( 1 ) , mice were injected intraperitoneally with human ovarian cancer-derived NIH:OVCAR-5 cells and subjected to PDT using BPD on days 10 and 20 after tumor cell inoculation. C225 was administered intraperitoneally on days 11, 14, 17, and 19 after tumor cell inoculation. As compared with mice treated with either C225 or PDT alone, mice treated with combined PDT + C225 showed a decrease in mean tumor burden as measured on day 21 after tumor cell inoculation and an increase in overall survival when mice were followed up to day 180, with three of nine C225 + PDT mice achieving cure of disease. When used separately, both intraperitoneally administered C225 and PDT have theoretical advantages that exploit different aspects of ovarian carcinoma tumor biology and may help make up for some of the defi ciencies in the current standard therapies. Through inhibition of EGFR signaling, C225 has the potential to inhibit both the survival and the spread of ovarian carcinoma cells, regardless of their resistance or sensitivity to chemotherapy. Autocrine growth factor signaling networks involving lysophosphatidic acid (LPA) and EGFR ligands such as heparinbinding epithelial-like growth factor (HB-EGF) have been implicated in the development of the malignant ovarian cancer phenotype, the intraperitoneal spread of ovarian tumors, the growth and survival of ovarian cancer cells, and the resistance of ovarian cancer cells to chemotherapy ( 2 – 4 ) . Activation of LPA receptors can act directly to stimulate carcinoma cell survival, growth, migration, and invasiveness ( 2 ) . Ovarian carcinoma cells have also been found to overexpress EGFRs, and EGFR overexpression has been associated with poor clinical outcome ( 5 ) . Conversely, inhibition of EGFR signaling by both smallmolecule and immunoglobulin-derived EGFR inhibitors leads to inhibition of ovarian carcinoma cell growth and survival ( 5 ) . In addition, cross-talk between LPA and EGFRs may occur at multiple levels: EDITORIALS C225 and PDT Combination Therapy for Ovarian Cancer: The Play’s the Thing

EDITORIALS and PDT Combination Therapy for Ovarian Cancer: The Play's the Thing

Abstract: The prognosis for women diagnosed with advanced-stage epithelial ovarian cancer is poor, with fewer than one-third of patients surviving 5 years. Locally advanced pelvic tumors are often associated with diffuse peritoneal carcinomatosis and bulky tumor lesions involving the omentum, bowel, mesentery, and diaphragmatic surface. Even after aggressive cytoreductive surgery and platinum-based chemotherapy, most of these patients experience local progression or recurrence. The reasons for treatment failure probably relate to diffi culties inherent to surgery within the peritoneal cavity, problems related to administering cytotoxic agents to the tumor cells in cytotoxic concentrations, and the ability of ovarian cancer cells to develop resistance to standard chemotherapies. In this issue of the Journal, del Carmen and colleagues ( 1 ) present evidence that intraperitoneal administration of C225, a humanized murine monoclonal antibody directed against the epidermal growth factor (EGF) receptor (EGFR), and benzoporphyrin derivative monoacid-A (BPD) – based photodynamic therapy (PDT) act synergistically to prevent or inhibit tumor cell growth and extend survival in a murine model of ovarian cancer peritoneal metastasis. In these studies ( 1 ) , mice were injected intraperitoneally with human ovarian cancer-derived NIH:OVCAR-5 cells and subjected to PDT using BPD on days 10 and 20 after tumor cell inoculation. C225 was administered intraperitoneally on days 11, 14, 17, and 19 after tumor cell inoculation. As compared with mice treated with either C225 or PDT alone, mice treated with combined PDT + C225 showed a decrease in mean tumor burden as measured on day 21 after tumor cell inoculation and an increase in overall survival when mice were followed up to day 180, with three of nine C225 + PDT mice achieving cure of disease.