Treatment outcome has improved in acute myeloid leukemia (AML), AML. To improve treatment outcomes in AML, there is a compelling need to develop treatments which attack novel cellular targets and which are not affected by known mechanisms of resistance. Irinotecan (CPT-11) is a topoisomerase I-interactive drug which, as a single agent, has shown limited activity against 5-florouracil (5-FU)-refractory colorectal cancer, but, in combination with 5-FU, is very effective against the disease both in preclinical models and in clinical trials. The efficacy of this combination is highly schedule-dependent. We have found that CPT-11 is highly active against multidrug-resistant human leukemia xenografts in vivo. Moreover, preclinical data from our laboratory demonstrate that the schedule-dependent synergistic drug interaction which has been found for CPT-11 and 5-FU also applies to CPT-11 in combination with Ara-C. Based on these preclinical findings, a Phase I clinical protocol was designed and initiated combining CPT-11 with Ara-C in the treatment of refractory AML and chronic myelogenous leukemia in myeloid blast transformation (CML-MBT). The objective of this application is to develop CPT-11 and Ara-C combination chemotherapy as a treatment for myeloid leukemias resistant to current therapies; this approach would then subsequently be applied to untreated AML with a low likelihood of response to current regimens.
The specific aims presented are: 1. To define the efficacy of CPT-11 and Ara-C combination chemotherapy in refractory AML and in CML-MBT; 2. To optimize the schedule of CPT-11 and Ara-C combination chemotherapy based on laboratory correlates of efficacy; and 3. To identify correlates of sensitivity and resistance to CPT-11 and Ara-C combination chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA089938-02
Application #
6378210
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Project Start
2000-09-30
Project End
2003-09-29
Budget Start
2001-09-30
Budget End
2003-09-29
Support Year
2
Fiscal Year
2001
Total Cost
$272,288
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Minderman, Hans; O'Loughlin, Kieran L; Smith, Patrick F et al. (2006) Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia. Cancer Chemother Pharmacol 57:73-83
Minderman, Hans; Conroy, Jeffrey M; O'Loughlin, Kieran L et al. (2005) In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther 4:885-900
Suvannasankha, A; Minderman, H; O'Loughlin, K L et al. (2004) Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function. Leukemia 18:1252-7
Minderman, Hans; Brooks, Tracy A; O'Loughlin, Kieran L et al. (2004) Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023. Cancer Chemother Pharmacol 53:363-9
Brooks, Tracy A; Kennedy, Daniel R; Gruol, Donald J et al. (2004) Structure-activity analysis of taxane-based broad-spectrum multidrug resistance modulators. Anticancer Res 24:409-15
Brooks, Tracy A; Minderman, Hans; O'Loughlin, Kieran L et al. (2003) Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Mol Cancer Ther 2:1195-205
Minderman, Hans; Suvannasankha, Attaya; O'Loughlin, Kieran L et al. (2002) Flow cytometric analysis of breast cancer resistance protein expression and function. Cytometry 48:59-65