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A pilot study of low dose hydroxyurea as a novel resistance modulator in metastatic renal cell cancer
1Ottawa Regional Cancer Centre, Cancer Care Ontario, and University of Ottawa, Canada.
Abstract:
Mechanisms of chemoresistance in renal cell carcinoma include P-glycoprotein, overexpression of multidrug resistance-1 (mdr1) gene, and unstable chromosomal aberrations. In vitro exposure of resistant tumor cells to low dose hydroxyurea causes loss of chromosomal aberrations, decrease in the mdr1 gene copies, and increased sensitivity to vinblastine. Patients received continuous hydroxyurea 500 mg every Monday, Wednesday and Friday. Vinblastine 5 mg/m2 was given intravenously on days 1 and 8 every 21 days. Seventeen patients with a median age of 63 (range 40-80) received a median of 3 courses of vinblastine (range 1-14). Toxicities included: > or = grade 3 non-hematologic toxicity (1) and febrile neutropenia (2). No treatment related mortality occurred. Three patients (17.6%) had partial responses. The median survival was 38.0 weeks (95% CI = 26.9-49.1 weeks). The addition of hydroxyurea given at the dose of 500 mg orally three times weekly had no major impact on the expected antitumor effect of vinblastine.
Insights
Hydroxyurea may reverse chemoresistance in renal cell carcinoma by reducing multidrug resistance-1 (mdr1) gene copies and chromosomal aberrations, potentially increasing sensitivity to vinblastine.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Renal cell carcinoma (RCC) exhibits chemoresistance due to mechanisms like P-glycoprotein and multidrug resistance-1 (mdr1) gene overexpression.
- Chromosomal aberrations are implicated in RCC chemoresistance.
Purpose of the Study:
- To investigate the potential of hydroxyurea to overcome chemoresistance in renal cell carcinoma.
- To evaluate the impact of hydroxyurea on mdr1 gene copies and chromosomal aberrations in vitro and in vivo.
Main Methods:
- In vitro studies exposed resistant tumor cells to low-dose hydroxyurea, assessing changes in chromosomal aberrations and mdr1 gene copies.
- A clinical trial administered hydroxyurea concurrently with vinblastine to RCC patients.
Main Results:
- In vitro, hydroxyurea reduced chromosomal aberrations and mdr1 gene copies, enhancing vinblastine sensitivity.
- Seventeen patients received treatment; 17.6% achieved partial responses, with a median survival of 38.0 weeks.
- Concurrent hydroxyurea did not significantly alter vinblastine's antitumor effect or survival.
Conclusions:
- Hydroxyurea demonstrates potential in vitro to reverse chemoresistance mechanisms in renal cell carcinoma.
- The addition of low-dose hydroxyurea did not substantially impact the clinical efficacy or survival outcomes of vinblastine treatment in RCC patients.