Synergistic therapy of breast cancer with Y-90-chimeric L6 and paclitaxel in the xenografted mouse model: development of a clinical protocol.
BACKGROUND
Paclitaxel (Taxol) has demonstrated synergistic enhancement of radioimmunotherapy (RIT) of breast cancer with Y-90 labeled antibody ChL6, in the xenografted mouse model. To determine the optimal sequence and timing of RIT and Taxol for a prospective clinical trial, efficacy and dosimetry in mice, and dosimetry in patients receiving RIT alone, were examined.


METHODS
Mice bearing human breast cancer xenografts (HBT 3477) received i.v. Y-90-DOTA-peptide-ChL6 (260 microCi), and i.p. Taxol (300 or 600 micrograms) 72, 48, or 24 hours prior to RIT, or 6, 24, 48, or 72 hours after RIT.


RESULTS
Taxol after RIT resulted in cure, CR, or PR of all mice (70/70 tumors) and demonstrated greater therapeutic enhancement (p = 0.001) than Taxol before RIT. Mice receiving 600 micrograms Taxol 48 hours after RIT achieved 88% cure (7/8 tumors). In mice, 57% and 42% of the radiation dose to tumor and marrow, respectively, was delivered from 48-336 hours after RIT; in patients receiving 90Y-DOTA-peptide-ChL6, the corresponding values were 56% and 22%.


CONCLUSIONS
Taxol given approximately 48 hours after RIT provides coincident peak deposition of Taxol and Y-90 in tumor, and no Taxol in the marrow during the major radiation dose to marrow, resulting in therapeutic enhancement without observable additive toxicity. A clinical trial of low dose Taxol given after RIT to patients with metastatic breast cancer is planned.
Denardo
S J
SJ
Section of Radiodiagnosis and Therapy, University of California Davis Medical Center, Sacramento, USA.
Richman
C M
CM
Kukis
D L
DL
Shen
S
S
Lamborn
K R
KR
Miers
L A
LA
Kroger
L A
LA
Perez
E A
EA
Denardo
G L
GL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000532:radiotherapy*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D005260:Female; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015019:Yttrium / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D006571:Heterocyclic Compounds; D009842:Oligopeptides; C112391:yttrium-90-DOTA-peptide-chimeric L6; D015019:Yttrium; D017239:Paclitaxel