Prognostic Impact of HIF-1α Expression in Patients with Definitive Radiotherapy for Cervical Cancer

PURPOSE: To investigate the relationship between the hypoxia-inducible factor-(HIF-)1alpha expression in tumor tissue, tumor oxygenation and hemoglobin levels in patients with advanced cervical cancers prior to radiotherapy and the effect on clinical outcome. PATIENTS AND METHODS: The investigation included 44 patients who underwent definitive radiotherapy for advanced cervical cancers between May 1995 and March 1999. Tumor biopsies were taken prior to treatment, and HIF-1alpha expression was determined by immunohistochemistry. In the same tumor area, tumor tissue oxygenation (pO2) was measured using the Eppendorf device. RESULTS: The 5-year cancer-specific survival of all patients was 60%. Twelve of 44 tumor specimens were HIF-1alpha-negative with a significantly better 5-year survival (92 +/- 8%) versus 32 patients who were HIF-1alpha-positive (45 +/- 10%; p < 0.02). There was no correlation between HIF-1alpha expression and tumor oxygenation (p = 0.57 both for pO2 median and hypoxic fraction < 5 mmHg vs. HIF-1alpha expression). However, patients with hemoglobin levels < 11 g/dl showed elevated HIF-1alpha expression compared to patients with hemoglobin levels > 12.5 g/dl (p = 0.04). Furthermore, HIF-1alpha correlated with vascular endothelial growth factor expression (p = 0.002). In a multivariate Cox regression model, HIF-1alpha expression (relative risk [RR] = 7.5; p = 0.05) revealed an increased risk of tumor-related death. CONCLUSION: The study indicates, that endogenous tumor markers such as HIF-1alpha may serve as prognostic markers of clinical outcome concerning cervical cancer after primary radiotherapy.     

Comparative cytotoxicity of CI-973, cisplatin, carboplatin and tetraplatin in human ovarian carcinoma cell lines

The clinical efficacy of cisplatin-based chemotherapy for ovarian cancer is frequently compromised by drug resistance or dose-limiting renal and neurologic toxicities. CI-973 (NK-121), a 2-methyl-1,4-butanediamine analogue of carboplatin, has shown little nephro- and neuro-toxicity in pre-clinical model systems and in phase-I trials. Its in vitro spectrum of activity against ovarian cancer cell lines has not been previously characterized. The in vitro activities of CI-973, cisplatin, carboplatin and tetraplatin were compared in several platinum-sensitive and -resistant human ovarian carcinoma cell lines. Cytotoxicity was assessed by inhibition of clonogenic survival in soft agar with continuous drug exposure. On a molar basis, cisplatin and tetraplatin were the most potent analogues, while carboplatin was consistently less potent. Cisplatin, carboplatin and CI-973 elicited a very similar response pattern by Spearman rank correlation, distinct from that seen with tetraplatin. The magnitude of resistance to CI-973 was comparable to cisplatin in 5 cell lines but was substantially lower in the highly cisplatin-resistant 2780-CP70 and OVCAR-10 cell lines. These results suggest that CI-973 and tetraplatin may have potential utility in some cases of cisplatin-resistant ovarian cancer. In addition, our data are consistent with the existence of at least 2 platinum-resistance phenotypes--one with moderate levels of resistance to cisplatin, carboplatin and CI-973 but highly resistant to tetraplatin, the other highly resistant to cisplatin and carboplatin but only partially cross-resistant with tetraplatin and CI-973. The recognition of different resistance phenotypes may facilitate the study of cellular resistance mechanisms to cisplatin and newer platinum analogues.