title: Response of human multiple myeloma-derived cell lines to alkyl-lysophospholipid.
abstract: Clinical studies using high-dose chemotherapy and autologous bone marrow transplantation in multiple myeloma report improvement in tumor regression. The potential success of this approach may be compromised because of the myeloma cell burden. A promising approach is chemopurging of bone marrow with alkyl-lysophospholipids (ALP), a new class of antitumor agents. Using a limiting dilution assay, we tested ALP against several drug-resistant human myeloma cell lines: RPMI 8226/S, 8226/DOX40, 8226/LR-5, 8226/MR-20, 8226/DOX1V, and 8226/MDR10V. IC50 values were approximately 6 microg/mL, for all cell lines evaluated. ALP was effective against all cells, with mean log kills ranging from 2.48 to 4.95. Cytotoxicity was temperature-dependent. Survival curves of cell lines exposed to ALP showed a steep slope during the first 4 hours of exposure, with little additional cell kill after 24 hours. Dose-response curves after drug exposure for 4 and 24 hours reached plateaus at 75 and 25 microg/mL, respectively. Increasing concentrations of ALP caused a sustained increase in resting [Ca2+]i of sufficient magnitude to induce cell death. These results suggest that ALP is an effective cytotoxic agent even in cells known to be resistant to alkylating agents and other classes of cytotoxic drugs.
authors.affiliation: Department of Pathology, College of Medicine, University of Arizona, Tucson, USA.
authors.forename: L
authors.initials: L
authors.lastname: Glasser
authors.forename: W S
authors.initials: WS
authors.lastname: Dalton
authors.forename: R L
authors.initials: RL
authors.lastname: Fiederlein
authors.forename: P
authors.initials: P
authors.lastname: Cook
authors.forename: G
authors.initials: G
authors.lastname: Powis
authors.forename: W R
authors.initials: WR
authors.lastname: Vogler
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D013696:Temperature; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010742:Phospholipid Ethers; C026659:edelfosine; D002118:Calcium