Failure to achieve effective chemotherapy in children with malignant solid tumors can be broken down into two main categories. The first is the inability to achieve appropriate drug concentrations. The second would be the tumor is refractory to treatment. A major cause of ineffective antitumor activity is poor uptake of a diverse array of cancer chemootherapeutics. This phenotype is referred to as multidrug resistance and some of the ATP binding cassette transporters have been strongly implicated in the lack of response to certain chemotherapeutics. However, these ABC transporters are not expressed in all pediatric solid malignancies. An inability to achieve appropriate drug concentrations can be due to poor absorption. The ABC transporters, most notably MDR1, have been demonstrated to play a critical role in absorption of chemotherapeutics. However, MDR1 has not been demonstrated to play a significant role in camptothecin absorption and systemic disposition. In the current studies we will focus on two ABC transporters that play a role in camptothecin uptake. The hypotheses of this project are: (1) BCRP/ABCG2 is important to the disposition of camptothecin analogues in vivo and the antitumor response to these agents; (2) MRP4 plays a significant role in the disposition and tumor response of camptothecin analogues; (3) the 4-aminoquinazoline (4-AQ; e.g., ZD1839) compounds interact with a variety of transport proteins, leading to altered disposition of concomitantly administered drugs; (4) BCRP/ABCG2 transcriptional regulation is dependent upon a novel signaling pathway; and (5) sequence variations in BCRP/ABCG2 and MRP4 impact their function.
These aims will be primarily addressed through a combination of biochemical and molecular biological studies and will use the unique Bcrp1 and mrp4 knockout animals to gain an insight into the disposition of camptothecin analogs that is likely based on their tissue distribution. Translation of the findings from this project will be incorporated into clinical studies to develop optimal dosing regimens and to verify the relationships identified in the animal models.
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