Effects of hydroxyurea on extrachromosomal DNA in patients with advanced ovarian carcinomas.
OBJECTIVE
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.


METHODS
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.
Raymond
E
E
Institute for Drug Development-Cancer Therapy and Research Center, San Antonio, Texas 78245-3217, USA. raymond@igr.fr
Faivre
S
S
Weiss
G
G
McGill
J
J
Davidson
K
K
Izbicka
E
E
Kuhn
J G
JG
Allred
C
C
Clark
G M
GM
Von Hoff
D D
DD
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002884:Chromosomes, Human, Pair 15; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000493:pharmacokinetics / Q000494:pharmacology*; D008677:Metaphase / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006918:Hydroxyurea