title: Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts.
abstract: Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. (90)Y-labeled DOTA-peptide-ChL6 ((90)Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and (90)Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving (90)Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before (90)Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after (90)Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with (90)Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to (90)Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with (90)Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with (90)Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.
authors.affiliation: Department of Internal Medicine, University of California Davis Medical Center, Sacramento 95816, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: DeNardo
authors.forename: D L
authors.initials: DL
authors.lastname: Kukis
authors.forename: L A
authors.initials: LA
authors.lastname: Kroger
authors.forename: R T
authors.initials: RT
authors.lastname: O'Donnell
authors.forename: K R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: L A
authors.initials: LA
authors.lastname: Miers
authors.forename: D G
authors.initials: DG
authors.lastname: DeNardo
authors.forename: C F
authors.initials: CF
authors.lastname: Meares
authors.forename: G L
authors.initials: GL
authors.lastname: DeNardo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D016499:Radioimmunotherapy; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000008:administration & dosage*
chemical_list: D000906:Antibodies; D000972:Antineoplastic Agents, Phytogenic; D015850:Interleukin-6; D015021:Yttrium Radioisotopes; D017239:Paclitaxel