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Effects of hydroxyurea on extrachromosomal DNA in patients with advanced ovarian carcinomas
1Institute for Drug Development-Cancer Therapy and Research Center, San Antonio, Texas 78245-3217, USA. raymond@igr.fr
Purpose:
In vitro low concentrations of hydroxyurea eliminate double-minute chromosomes (dmins) containing amplified drug-resistance genes and oncogenes from cancer cells. This clinical trial investigated whether a noncytotoxic dose of oral hydroxyurea could reduce the number of dmins in cancer cells in patients with advanced ovarian carcinomas.
Experimental Design:
The high frequency of ascites associated with ovarian cancer facilitated the monitoring of cytogenetic variations with minimal discomfort in patients who required frequent abdominal paracentesis. Sixteen patients with advanced ovarian carcinomas resistant to conventional cisplatin-based and/or paclitaxel chemotherapy and with ascites requiring frequent abdominal paracentesis were entered in this study. A course of treatment consisted of a single oral dose of 80 mg/kg hydroxyurea every 3 days for 6 weeks. Blood and i.p. levels of hydroxyurea were determined. We monitored the variations of dmins in tumor cells taken from serial abdominal paracenteses.
Results:
The median number of courses administered to the patients was 1 (range, 1--9). In ascites, hydroxyurea concentrations were 610.3 +/- 76.3, 219.8 +/- 85.6, and 86.1 micromol/liter at 4, 24, and 30 h after oral administration, respectively. Eleven (78.6%) of 14 patient specimens contained dmins before therapy. The number of spreads with tumor cells containing dmins were reduced by more than 50% in 5 (45%) of 11 and 3 (60%) of 5 patients at the completion of the first and second course of chemotherapy, respectively. Using tumor cells taken directly from the patients and grown in soft agar, we documented that concentrations of hydroxyurea in ascites were too low to have any cytotoxic effects. No grade 3--4 hydroxyurea-related toxicities nor any objective responses were observed. However, despite the utilization of a low noncytotoxic dose of hydroxyurea, two patients had prolonged stabilization of their disease for 6 and 10 months, respectively, with concomitant decreases in the number of dmins that remained until progression.
Conclusions:
This study showed that, in some circumstances, a noncytotoxic dose of hydroxyurea given to patients with ovarian cancer can decrease the number of metaphase spreads containing dmins in cancer cells.
Insights
A noncytotoxic dose of hydroxyurea reduced double-minute chromosomes (dmins) in ovarian cancer cells. This finding suggests a potential new therapeutic strategy for ovarian cancer by targeting dmins without causing significant toxicity.
Area of Science:
- Oncology
- Cancer Genetics
- Pharmacology
Background:
- Double-minute chromosomes (dmins) are associated with drug resistance and oncogene amplification in cancer.
- Hydroxyurea has demonstrated in vitro efficacy in eliminating dmins from cancer cells.
Purpose of the Study:
- To investigate the effect of a noncytotoxic oral dose of hydroxyurea on reducing dmins in patients with advanced ovarian carcinomas.
- To assess the feasibility and safety of this treatment approach in a clinical setting.
Main Methods:
- A clinical trial involving 16 patients with advanced ovarian cancer and ascites.
- Treatment consisted of oral hydroxyurea (80 mg/kg) every 3 days for 6 weeks.
- Monitoring of dmins in tumor cells from serial abdominal paracenteses and hydroxyurea levels in ascites.
Main Results:
- Hydroxyurea concentrations in ascites were noncytotoxic.
- A reduction in dmins was observed in 45% of patients after the first course and 60% after the second course.
- Two patients experienced prolonged disease stabilization (6 and 10 months) with decreased dmins.
Conclusions:
- A noncytotoxic dose of hydroxyurea can decrease the number of metaphase spreads containing dmins in ovarian cancer cells.
- This approach may offer a novel therapeutic strategy for ovarian cancer, warranting further investigation.