Modulation of clinical drug resistance in a B cell lymphoma patient by theprotein kinase inhibitor 7-hydroxystaurosporine: Presentation of a novel therapeutic paradigm

Emerging evidence suggests that apoptosis is an important mechanism of tumo r cell death from antineoplastic therapy. 7-hydroxystaurosporine (UCN-01) i s a novel protein kinase inhibitor that increases chemotherapy-induced apop tosis in vitro and is in early phases of clinical development. In this repo rt, we present a 68-year-old patient with chemotherapy-resistant lymphoma t reated with UCN-01 and chemotherapy, He had a stage IV plasmacytoid lymphom a that failed to enter remission with high-dose EPOCH LI (etoposide, predni sone, vincristine, cyclophosphamide, doxorubicin) chemotherapy, Due to dise ase progression and transformation to large cell lymphoma in the liver and bone marrow, he received UCN-01, Four weeks later, he received "standard-do se" EPOCH because of progression, developed severe neutropenia for 9 days, and expired from Candida sepsis on day 23, At autopsy, there was no histolo gical evidence of residual lymphoma, although PCR for immunoglobulin gene r earrangement analysis revealed a faint clonal band in two of six nodes but none in the liver. Significantly, no B cells were detected by immunohistoch emistry in lymph nodes, and a polyclonal ladder pattern associated with the presence of normal B cells was not seen in the immunoglobulin gene rearran gement PCR assay. Profound peripheral lymphopenia (50 cells/mu I) was also observed. Pharmacokinetics showed UCN-01 salivary concentrations, a surroga te for free drug concentrations, to be within an effective range in vitro ( 45 mmol/L) as a modulator of DNA-damaging agent cytotoxicity. In vitro, UCN -01 is synergistic with multiple cytotoxic agents and increases fludarabine -induced apoptosis in a human breast cell line. These results suggest that UCN-01 sensitized the lymphoma to the cytotoxic effects of EPOCH, possibly by modulating the "threshold" for apoptosis, and may illustrate a new parad igm for reversal of drug resistance.