sdx-308 and Leukemia--Lymphocytic--Chronic--B-Cell

Non-steroidal anti-inflammatory drugs have been shown to inhibit carcinogenesis in colon cancer, and to induce apoptosis in a variety of tumor cell lines. Some anti-tumor effects are thought to be related to their cyclooxygenase-2-inhibitory activity, but recent studies have shown that non-steroidal anti-inflammatory drugs exert their anti-tumor effect via cyclooxygenase-2-independent mechanism. SDX-308 (CEP-18082) is a non-cyclooxygenase-2-inhibiting indole-pyran analog and is structurally related to SDX-101, an R-enantiomer of etodolac. SDX-308 has a potent anti-myeloma effect and shows synergism in combination with other drugs for the treatment of chronic lymphocytic leukemia. In addition SDX-308 inhibits osteoclast formation and activity and thereby might be an attractive drug for the treatment of diseases with increased osteoclast activity such as osteolytic lesions in multiple myeloma and metastatic carcinomas, as well as osteoporosis. This review covers future application of SDX-308 as an anti-myeloma drug regulating increased osteoclast activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Etodolac; Hematologic Neoplasms; Heterocyclic Compounds, 3-Ring; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; NF-kappa B; Osteoclasts; Stereoisomerism

SDX-101 is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac, and has anti-tumour activity in chronic lymphocytic leukaemia (CLL). SDX-308 and SDX-309 are more potent, structurally related indole-pyran analogues of SDX-101. The current study was performed to investigate and quantify the cytotoxic potentiating effects resulting from a combination of either SDX-101, SDX-308 or SDX-309 with standard cytotoxic agents used in the CLL treatment today.. The lymphoma cell line U937-gtb was used, together with primary tumour cells isolated from seven CLL patients. Combinations between chlorambucil and each one of the agents etodolac, SDX-101, SDX-308 and SDX-309 were studied. In addition, SDX-309 was combined with fludarabine, doxorubicin or vincristine. Both simultaneous and sequential exposures were explored using the median-effect method.. Most combinations were additive, which could be of clinical benefit since SDX-101 has been shown to be well tolerated. At the 70% effect level, synergy was observed between SDX-308 and chlorambucil in U937-gtb cells and in two-third of the CLL samples. Since chlorambucil is the most important drug in CLL therapy today and SDX-308 is presently targeted as the lead clinical candidate, this combination would be interesting for further studies. Vincristine and SDX-309 were synergistic in two-fourth of CLL samples.. To conclude, the non-COX-inhibiting etodolac-derivatives SDX-101, SDX-308 and SDX-309 are potential candidates for combination treatment of CLL. Especially, SDX-308 in combination with chlorambucil warrants further evaluation.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chlorambucil; Doxorubicin; Drug Synergism; Etodolac; Female; Heterocyclic Compounds, 3-Ring; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Male; Middle Aged; Vincristine