Cytotoxic chemotherapy regimens that increase dose per cycle (dose intensity) by extending daily dosing from 5 consecutive days to 28 consecutive days and beyond

Dose intensity, defined as dose administered per unit time, has emerged as a potentially important measurement of anticancer drug exposure and determi nant of efficacy. There are several strategies for increasing dose intensit y, one being a protracted daily dosing strategy without major dose reductio n for toxicity. This strategy involves continued therapy during periods of recovery from reversible toxicity, and it inherently challenges our underst anding that renewing tissues cannot repopulate (recover) in the continued p resence of cytotoxic drug. We have tested this idea directly in a murine pr eclinical trial. Specifically, we have tested whether acutely myelotoxic do ses of gemcitabine (i.p. injection, 6.0 mg/m(2)/day), acetyldinaline [CI-99 4; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide, 150 mg /m(2)/day p.o.], and/or melphalan (i.p. injection, 7.2 mg/m(2)/day) can be tolerated for 28 consecutive days and whether suppressed bone marrow functi on recovers despite this protracted daily therapy. The three drugs all caus ed acute neutropenia and suppression of medullary hematopoiesis, Damage to progenitor populations exposed to acetyldinaline and gemcitabine was not as severe as that caused by melphalan, in which case absolute neutrophil coun t, mature progenitors (colony-forming unit granulocyte/macrophage), and imm ature progenitors (colony-forming unit-S) progressively declined to severel y depressed levels. Marrow recovery was observed during continued daily tre atment with acetyldinaline and gemcitabine but not melphalan, and marrow fu nction completely recovered after finishing the 28-day course. Pharmacology studies proved that protracted therapy causes little, if any, change in ce llular drug tolerance or systemic exposure.