Biomedical subjects
Naomi B Haas
Publications and source records attributed to Naomi B Haas.
Macrophage migration inhibitory factor is a determinant of hypoxia-induced apoptosis in colon cancer cell lines.
Hypoxia contributes to cytotoxic chemotherapy and radiation resistance and may play a role in the efficacy of antiangiogenesis cancer therapy. We have generated a series of cell lines derived from the colon adenocarcinoma models HT29 and HCT116 by exposing cells in vitro to repeated sublethal periods of profound hypoxia. These cell lines have altered sensitivity to hypoxia-induced apoptosis: those derived from HT29 are resistant, whereas those from HCT116 are more susceptible. We used cDNA selected subtractive hybridization to identify novel genes mediating sensitivity to hypoxia-induced apoptosis and isolated macrophage migration inhibitory factor (MIF) from the hypoxia-conditioned cell lines. MIF expression correlates with susceptibility of the cell lines to apoptosis. In hypoxia-resistant cells, the induction of apoptosis by hypoxia can be restored by the addition of exogenous recombinant MIF protein, suggesting that resistance may result in part from down-regulation of MIF production possibly through an autocrine loop. Inhibition of MIF using small interfering RNA in the susceptible lines conferred resistance to hypoxia-induced cell death. The relative expression of MIF in the hypoxia-conditioned cells implanted s.c. in severe combined immunodeficient mice in vivo was similar to that observed in vitro. In an analysis of 12 unrelated colon tumor cell lines, MIF expression and response to hypoxia varied widely. Cell lines in which MIF was inducible by hypoxia were more sensitive to oxaliplatin. In human colon tumor specimens analyzed by immunohistochemistry, MIF expression was similarly variable. There was no detectable expression of MIF in normal colon mucosa or adenoma but positive staining in all carcinomas tested. Taken together, these data indicate that MIF may be a determinant of hypoxia-induced apoptosis in vitro and that its variable expression in human colon cancers may indicate a functional role in vivo. We suggest that MIF expression in colorectal cancer may be a marker of susceptibility to therapies that may depend on induction of hypoxia, possibly including antiangiogenic therapy.
Vinblastine and estramustine phosphate in metastatic renal cell carcinoma: a phase II trial of the Fox Chase Network.
BACKGROUND: It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine. The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine. METHODS: Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy. RESULTS: Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks. CONCLUSIONS: Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC.
Weekly bryostatin-1 in metastatic renal cell carcinoma: a phase II study.
PURPOSE: We conducted a Phase II trial of bryostatin-1, an inhibitor of protein kinase C, in advanced renal cell carcinoma to measure toxicity, response rate, time to progression, and induction of cytokines. EXPERIMENTAL DESIGN: A total of 32 patients (26 male and 6 female) received bryostatin-1 at 35-40 microg/m(2) i.v. over 1 h on days 1, 8, and 15 of each 4-week cycle. Plasma interleukin-6, tumor necrosis factor-alpha, and C-reactive protein levels were assayed pretreatment, 1 and 23 h after completion of bryostatin-1 infusion at weeks 1 and 5. RESULTS: Cycles (102) of bryostatin-1 were given (median 2, range 1-8). The most common grade 1 or 2 toxicities were myalgias (46.8%), fatigue (59.3%), and dyspnea (18.8%). Grade 3-4 toxicity included myalgias (40.6%), ataxia (9.3%), and dyspnea (15.6%). Four (12%) patients experienced cardiac events while on study (cardiac arrhythmias and congestive heart failure occurred in 2 patients, and 2 patients had fatal cardiac arrests). Of 32 patients evaluable for response, 2 (6.3%) had partial responses lasting 9 with 6 months. A total of 15 patients (46.8%) had stable disease, and 6 (18.8%) patients had stable disease for >or=6 months. Plasma interleukin-6 increased >or=2-fold over baseline measurements in 5 of 17 patients (29.4%) but did not correlate with response or toxicity. CONCLUSIONS: Although weekly bryostatin-1 at 35-40 microg/m(2) produced a low proportion of objective responses, prolonged (>6 months) stable disease or partial remission in 25% of patients suggests that this agent, or other inhibitors of protein kinase C, may have a role in the treatment of renal cell carcinoma, perhaps in combination with other agents.