Cross-resistance patterns in hydroxyurea-resistant leukemia L1210 cells.

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Hydroxyurea is a ribonucleotide reductase inhibitor targeting the enzyme's non-heme iron subunit.
• Acquired resistance to chemotherapy is a significant challenge in treating leukemia.
• Understanding drug resistance mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

• To investigate the mechanisms of hydroxyurea resistance in L1210 leukemia cells.
• To characterize the cross-resistance and sensitivity profiles of hydroxyurea-resistant cells.
• To examine alterations in ribonucleotide reductase activity in resistant cell lines.

Main Methods:

• Culturing L1210 leukemia cells with increasing hydroxyurea concentrations to induce resistance.
• Determining drug concentrations required for 50% growth inhibition (IC50) for various inhibitors.
• Measuring ribonucleotide reductase activity (CDP and ADP reductase) in wild-type and resistant cell extracts.
• Assessing the effect of exogenous effector-binding subunit on reductase activity.

Main Results:

• Hydroxyurea-resistant (HU-7-S7) L1210 cells exhibited a significant increase in hydroxyurea resistance (2000 microM vs. 85 microM).
• HU-7-S7 cells showed cross-resistance to certain inhibitors but remained sensitive to others targeting the same or different subunits.
• Ribonucleotide reductase activity was substantially elevated in HU-7-S7 cells (5.5-fold for CDP, 13.2-fold for ADP reductase).
• Exogenous effector-binding subunit caused greater stimulation of reductase activity in resistant cells.

Conclusions:

• Increased ribonucleotide reductase activity contributes to hydroxyurea resistance in L1210 cells.
• The specificity of resistance depends on the inhibitor's target subunit.
• These findings highlight the complex nature of drug resistance to ribonucleotide reductase inhibitors.