Hydroxyurea and trimidox enhance the radiation effect in human pancreatic adenocarcinoma cells

Pancreatic cancer remains the most lethal of all common human malignancies with a 5-year survival rate of lower than 5%. Adjuvant and neoadjuvant preoperative and postoperative chemo-radiotherapy using 5-fluorouracil, have reduced local relapse rate and slightly increased the median survival. Testing new and more potent radiation-sensitising drugs in human pancreatic cancer cells can provide the basis for a more effective chemo-radiation regimen and may consequently improve treatment outcome.

The present study was performed to evaluate the efficacy of two potent ribonucleotide reductase (RR) inhibitors: hydroxyurea and trimidox in radio-sensitising Panc-1 human pancreatic cancer cells in an attempt to identify a more effective chemo-radiotherapy regimen with minimal side effects.

Treatment of Panc-1 cells with hydroxyurea or trimidox alone for 2 hours was associated with a dose-dependent decrease in their cloning efficacy to similar extent. The IC50 of trimidox, hydroxyurea or radiation alone were 2.5 + 0.3 microM, 39.0 + 0.4 microM and 3.2 + 0.2 Gy, respectively. Treatment with 39.0 microM non-cytotoxic IC50 dose of hydroxyurea for two hours before or immediately after radiation reduced the IC50 of radiation to only 1.1 + 0.14 or 1.0 + 0.1 Gy, respectively. Treatment with 2.5 microM non-cytotoxic IC50 dose of trimidox for two hours before or immediately after radiation reduced the IC50 of radiation to only 1.2 + 0.16 or 1.4 + 0.12 Gy, respectively. The mean radiation enhancement ratios were 2.9 and 3.2 for hydroxyurea before and immediately after radiation. The greater radio-sensitising effect of hydroxyurea compared to trimidox or gemcitabine could be due to its unique double action by synchronising the cancer cells into the radiosensitive G1/S border and inhibiting DNA damage repair.

The present study demonstrates the superiority of hydroxyurea at non-cytotoxic doses compared to the other two recent RR inhibitors: gemcitabine and trimidox in radio-sensitising human pancreatic cancer cells. Hydroxyurea combined with radiation has significantly improved progression-free survival of advanced cervical cancer and glioblastoma patients and showed clinical benefit in combination with other chemotherapy drugs in advanced pancreatic cancer. The present results suggest the clinical use of hydroxyurea as a radiosensitiser in both pre- and post-operative chemo-radiotherapy in pancreatic cancer patients. Given the demonstrated potent radio-sensitising effect of hydroxyurea at non-cytotoxic doses when administered before or immediately after radiation and its low clinical toxicity, it should be feasible to administer hydroxyurea both before and after radiation in pancreatic cancer patients.