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Pyrazoloacridine Is Active in Multidrug-resistant Neuroblastoma Cell Lines with Nonfunctional p53¹

Division of Hematology-Oncology, Children’s Hospital Los Angeles, and Departments of Pediatrics [N. K., C. P. R.], Pathology [C. P. R.], and Preventive Medicine [D. T-W.], University of Southern California Keck School of Medicine, Los Angeles, California 90033

Purpose: The purpose of this study was to determine the activity of pyrazoloacridine (PZA) in neuroblastomas that have acquired high-level resistance to multiple drugs (not associated with multidrug resistance-associated protein or P-glycoprotein) during therapy, including those with loss of p53 function.

Experimental Design: We determined the activity of PZA in 12 drug-sensitive and 10 multidrug-resistant (MDR) neuroblastoma cell lines. Six of the MDR cell lines lacked functional p53. Drug cytotoxicity was measured using the DIMSCAN fluorescence/digital imaging microscopy assay with a 4-log dynamic range.

Results: LC₉₀ (i.e., the drug concentration that was lethal for 90% of the cell population) values ranged from 0.01 to 1.1 µM for the drug-sensitive cell lines, from 0.8 to 2.4 µM for the MDR cell lines with functional p53, and from 0.9 to 2.1 µM for the MDR cell lines that lacked functional p53. To confirm that PZA cytotoxicity is independent of p53 function, we compared two neuroblastoma cell lines in which p53 function was abrogated via human papilloma virus-16 E6 transduction (which mediates increased degradation of p53) to the mock-transduced (LXSN) controls. LC₉₀ values for human papilloma virus-16 E6 clones (abrogated p53) ranged from 0.2 to 2.04 µM, whereas LC₉₀ values for LXSN controls (functional p53) were 0.1 and 0.5 µM. PZA was active with 72-h in vitro exposures against p53-nonfunctional MDR cells at drug levels (2–3 µM) obtained for shorter periods (1–3 h) in Phase I and II clinical trials. Washout experiments showed that 3 µM PZA achieved 0.5–1 log of cell kill with 1–3-h exposures versus 3 logs at 24 h.

Conclusions: These data suggest that expanding the time of PZA systemic exposure, which may be clinically tolerable with hematopoietic stem cell support, should be tested in clinical trials. Prolonged systemic exposure to PZA with hematopoietic stem cell support may be effective against recurrent neuroblastomas that have failed conventional chemotherapeutic regimens, including those neuroblastomas with loss of p53 function.

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