sdz-psc-833 and Lymphoma--Non-Hodgkin

The effect of CMC-544, a calicheamicin-conjugated anti-CD22 monoclonal antibody, was analysed in relation to CD22 and P-glycoprotein (P-gp) in B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) in vitro. The cell lines used were CD22-positive parental Daudi and Raji, and their P-gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B-cell CLL or NHL were also used. The effect of CMC-544 was analysed by viable cell count, morphology, annexin-V staining, and cell cycle distribution. A dose-dependent, selective cytotoxic effect of CMC-544 was observed in cell lines that expressed CD22. CMC-544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC-544 in P-gp-expressing sublines. In clinical samples, the cytotoxic effect of CMC-544 was inversely related to the amount of P-gp (P = 0.003), and to intracellular rhodamine-123 accumulation (P < 0.001). On the other hand, the effect positively correlated with the amount of CD22 (P = 0.010). The effect of CMC-544 depends on the levels of CD22 and P-gp. Our findings will help to predict the clinical effectiveness of this drug on these B-cell malignancies, suggesting a beneficial effect with combined use of CMC-544 and MDR modifiers.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Count; Cell Line, Transformed; Cell Line, Tumor; Cyclosporins; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Immunosuppressive Agents; Inotuzumab Ozogamicin; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Quinolines; Sialic Acid Binding Ig-like Lectin 2; Treatment Outcome; Tumor Cells, Cultured

The semiautomated fluorimetric microculture cytotoxicity assay (FMCA) was used for evaluation of the ability of cyclosporin A (CsA) and its novel non-immunosuppressive derivative SDZ PSC 833 (PSC) to modify the response to doxorubicin or vincristine in vitro in different haematological and solid human tumour types. Primary cultures of 322 tumour samples were analysed. Both cyclosporins showed resistance-modifying activity in all haematological tumours tested, and in solid tumours activity was observed in ovarian carcinoma and childhood tumours. Little or no effect was found in the remaining tumour types, including breast, renal and adrenal cortical carcinomas and adult sarcomas. In most of the responsive cases the interaction between the modifier and the cytotoxic drug was synergistic. There was a tendency to higher activity in samples from previously treated patients, and an inverse relationship between degree of cytotoxic drug resistance and resistance-modifying activity was noted. No difference in potency between CsA and PSC could be discerned. The results indicate differential in vitro resistance-modifying activity of the cyclosporins depending on tumour type. The results also suggest that treatment with resistance modifiers should be considered also for primary therapy of drug-sensitive tumours. Drug resistance assays such as the FMCA may become useful in preclinical evaluation of resistance modifiers.

Topics: Antineoplastic Agents; Child; Cyclosporine; Cyclosporins; Doxorubicin; Drug Interactions; Drug Resistance; Drug Screening Assays, Antitumor; Drug Synergism; Female; Fluorometry; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Ovarian Neoplasms; Tumor Cells, Cultured; Vincristine