Signaling via the anti-CD30 mAb SGN-30 sensitizes Hodgkin's disease cells to conventional chemotherapeutics.
SGN-30, a monoclonal antibody with activity against CD30+ malignancies, is currently in phase II clinical evaluation for treatment of Hodgkin's disease (HD) and anaplastic large cell lymphoma. The mechanisms underlying SGN-30's antitumor activity were investigated using cDNA array of L540 cells. SGN-30 treatment activated NF-kappaB and modulation of several messages including the growth regulator p21WAF1/CIP1 (p21) and cellular adhesion marker ICAM-1. p21 protein levels increased coincident with growth arrest and Annexin V/PI staining in treated HD cells. To determine if SGN-30-induced growth arrest would sensitize tumor cells to chemotherapeutics used against HD, L540cy and L428 cells were exposed to SGN-30 in combination with a panel of cytotoxic agents and resultant interactions quantified by the Combination Effects Method. Interactions between SGN-30 and all cytotoxic agents examined were additive or better. These in vitro data translated to increased efficacy of SGN-30 and bleomycin against L540cy tumor xenografts. In addition to direct cell killing, SGN-30 affects growth arrest and drug sensitization through growth regulating and proapoptotic machinery. Importantly, these data suggest that SGN-30 can enhance the efficacy of standard chemotherapies used to treat patients with CD30+ malignancies.
Cerveny
C G
CG
Department of Molecular Oncology and Immunology, Seattle Genetics, Inc., Bothell, WA 98021,USA.
Law
C-L
CL
McCormick
R S
RS
Lenox
J S
JS
Hamblett
K J
KJ
Westendorf
L E
LE
Yamane
A K
AK
Petroziello
J M
JM
Francisco
J A
JA
Wahl
A F
AF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017730:Ki-1 Antigen / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; D017730:Ki-1 Antigen; D016328:NF-kappa B; D001761:Bleomycin; C504717:SGN-30 monoclonal antibody