The emergence of acquired resistance to carboplatin therapy.

<p>DNA-mismatch repair in arrested cells recovering to the proliferating population is assumed to be the cause of resistance. The treatment of a late-stage tumor is simulated. Plots show 7 day-averages of carboplatin-sensitive (blue curve), carboplatin-resistant (red curve) and total (dashed black curve) tumor cell numbers versus time, as treatment strategy is varied. In all cases, therapy is administered for a period of 1 year. Increasing the weekly bolus dose of carboplatin administered as a single agent from <b>A</b>, 30 mg/kg, <b>B</b>, 300 mg/kg, to <b>C</b>, 800 mg/kg, cannot prevent the emergence of carboplatin-resistance. <b>D</b>, In fact, a weekly dose of 1300 mg/kg carboplatin is required to induce tumor regression. <b>E</b>, A combination of 30 mg/kg carboplatin delivered weekly as a bolus together with 100 mg/kg ABT-737 delivered daily is predicted to prevent the emergence of resistance and lead to tumor growth control at 6.5% of pre-treatment levels. <b>F</b>, The same combination dose, with carboplatin delivered via a 8-hour infusion is predicted to induce tumor regression within 150 days.