VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors

BACKGROUND: Pheochromocytomas are well-vascularized tumors of the adrenal medulla. In human pheochromocytomas, angiogenesis has been associated with tumor progression. The mechanisms, however, are unknown. METHODS: Surgical specimens of benign, invasive, and metastatic human pheochromocytomas (n = 10/5/5) were immunostained for vascular endothelial growth factor (VEGF) and CD34, to determine VEGF expression and microvessel density (vascular surface density, [VSD]). In PC12-pheochromocytoma cells, VEGF messenger RNA and protein were analyzed by Northern blotting and enzyme immunoassay; biologic activity by human umbilical vein endothelial cell-proliferation assay. Inhibition of angiogenesis of PC12 xenografts by 2 neutralizing anti-VEGF antibodies (C20-pAB, M461-mAB) was evaluated by VEGF expression, VSD, and mitotic activity. RESULTS: VEGF expression and VSD were significantly higher in metastatic pheochromocytomas (VEGF 37.1 +/- 10.9% vs 20.7 +/- 9%, VSD 26.2 +/- 8 vs 13.5 +/- 3.3 1/mm). VEGF messenger RNA and protein were confirmed in PC12 cells and stimulated by nerve growth factor. Conditioned PC12 medium increased human umbilical vein endothelial cell proliferation more than 2-fold. Xentrotransplanted PC12 cells had marked VEGF expression and angiogenesis, which was inhibited by anti-VEGF antibodies (VEGF-expression by 29 and 38%, VSD by 43 and 46%, P <.05). CONCLUSION: Higher VEGF expression and microvessel density in malignant pheochromocytomas suggest VEGF-mediated angiogenesis to be related to tumor progression. Angiogenesis of PC12 xenografts is mediated by VEGF. Neutralizing anti-VEGF antibodies inhibit angiogenesis in experimental pheochromocytomas and may have potential for treating nonresectable pheochromocytomas.     

New cadinene sesquiterpenoids from the Formosan soft coral Xenia puerto-galerae

Six new cadinene sesquiterpenoids, xenitorins A-F (1-6), were isolated from the methylene chloride solubles of the Formosan soft coral Xenia puerto-galerae. The structures were elucidated by 1D and 2D NMR spectral analysis, and their cytotoxicity against selected cancer cells was measured in vitro.     

Death from thyroid cancer of follicular cell origin

Background: Although patients with differentiated thyroid cancer (DTC) of follicular cell origin usually have an excellent prognosis, some patients die from progressive tumor. Numerous postoperative criteria have been used to predict prognosis in patients with DTC. The purpose of this investigation was to determine whether the TNM and metastases, age, completeness of resection, invasion, size (MACIS) classifications predicted survival time and why patients died from DTC. The extent of initial treatment and causes of death were also evaluated in these patients who died from thyroid cancer.

Study Design: Between 1965 and 1995, 102 of 1,224 patients with DTC treated at the University of California at San Francisco (UCSF) and UCSF/Mount Zion Medical Centers died from DTC. Risk factors including age at diagnosis, gender, histologic characteristics, TNM and MACIS classifications, the intervals among initial treatment, recurrence, and death, and the initial and subsequent treatments were documented in these 102 patients.

Results: Among the 102 patients who died of DTC 50% were men and 50% were women. The mean age of patients with DTC at diagnosis was 58 years at recurrence, 62 and 65 years at death. Thirty percent of these patients initially had unilateral thyroid operations and 70% had a bilateral operation. Tumors at presentation ranged from 0.6 to 13.0 cm (mean 4.4 cm); 46% of patients presented with late-stage tumors (TNM stage III, IV; MACIS score > 8). At presentation 46% of the patients had locally recurrent disease or regional metastases and 18% had distant metastases. Patients with persistent disease had a significantly shorter survival time than those with recurrent disease (p < 0.001). Both TNM and MACIS classifications were good predictors of survival time. Reoperations were performed in 51% of papillary, 26% of follicular, and 67% of Hürthle cell thyroid cancer patients. Fifty percent of patients with papillary thyroid cancer, 50% of patients with Hürthle cell thyroid cancer, and 11% of patients with follicular cell thyroid cancer died of locally advanced disease.

Conclusions: As expected, patients with local or regional recurrence and those with TNM stage I or MACIS score < 6 survived longer than patients with distant metastasis and TNM stage III or IV, MACIS score > 6, but some patients thought to be at low risk (TNM stage I; MACIS < 6) also died from thyroid cancer.     

A cytotoxic lobane diterpene from the formosan soft coral Sinularia inelegans

A new cytotoxic lobane diterpene, ineleganene (1), was isolated from the Formosan soft coral Sinularia inelegans. The structure of compound 1 was determined by 1D and 2D spectral analysis.     

A new experimental model for secondary hyperparathyroidism

We have developed an animal model to study the pathogenesis of secondary hyperparathyroidism by inducing stable uremia in Sprague-Dawley rats by selective microligation of terminal branches of the left renal artery, followed by right nephrectomy. After 4 weeks the animals were killed, the parathyroid glands were removed and weighed, and blood samples were obtained. Of 30 rats, uremia developed in 22 (73%; uremic group) and eight (27%) died or did not become uremic. A sham-operated group of 15 rats served as control (control group). Creatinine levels were 1.8 +/- 0.5 mg/dl in the uremic group versus 0.5 +/- 0.1 mg/dl in the control group (p less than 0.0001). Parathyroid glands were hyperplastic in all rats with uremia and were heavier than parathyroid glands of control animals (70.3 +/- 26 vs 19.1 +/- 8 micrograms; p less than 0.0001). In the group with uremia, parathyroid hormone levels were increased over those of the control group (112.6 +/- 13 vs 28.9 +/- 6.2 pg/ml; p less than 0.0001), whereas osteocalcin levels were similar (36.6 +/- 11 vs 37.5 +/- 1 ng/ml). Serum calcium, phosphate, and alkaline phosphatase levels were similar in both groups. Our model can be used to test hypotheses concerning the treatment of secondary hyperparathyroidism and the relative pathogenetic relevance of vitamin D deficiency and phosphate retention.     

Cytotoxic and anti-platelet aggregation constituents from the root wood of Melicope semecarpifolia

A new acetophenone derivative, melicopone, along with twenty-nine known compounds has been isolated from the root wood of Melicope semecarpifolia. The structure of this new compound was determined using spectral analyses. The compound oxynitidine isolated in this study adds the Melicope genus to the benzo[c]phenanthridine-containing members chemotaxonomically. Three isolates were cytotoxic in P-388 and HT-29 cell lines, and anti-platelet aggregation activities were shown for 10 known compounds.