Importance of temporal relationships in combined modality radioimmunotherapy of breast carcinoma.
BACKGROUND
The beneficial effects of radioimmunotherapy (RIT) may result from activation of molecular pathways that lead to programmed cell death (apoptosis). The influences of sequence and timing of 90Y-DOTA-peptide-ChL6 antibody (90Y-ChL6) and anti-epidermal growth factor receptor antibody (ch225) or paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) on efficacy and toxicity were examined.


METHODS
Groups of human breast carcinoma (HBT 3477) tumored mice received paclitaxel (300 or 600 microg) or ch225 (70, 150, or 350 microg) at various intervals before or after 90Y-ChL6. Mortality, hematologic toxicity, weight loss, and therapeutic efficacy were evaluated.


RESULTS
Mice receiving paclitaxel within 24 hours of 90Y-ChL6 had a 100% response rate; 48% were cured when paclitaxel was given 6 or 24 hours after 90Y-ChL6. When 150 microg ch225 was given 24 hours before 90Y-ChL6, the response and cure rates surpassed those of 90Y-ChL6 alone. Timing of administration was critical, with mortality rates as high as 80% in some groups receiving 350 microg ch225 and 90Y-ChL6.


CONCLUSIONS
In this aggressive human breast carcinoma model, combined 90Y-ChL6 and paclitaxel had a high therapeutic index with many cures. Sequence of administration was critical in order for ch225 or paclitaxel, when combined with 90Y-ChL6, to enhance the response rate.
DeNardo
S J
SJ
Department of Internal Medicine, University of California Davis Medical Center, Sacramento, USA.
Kroger
L A
LA
Lamborn
K R
KR
Miers
L A
LA
O'Donnell
R T
RT
Kukis
D L
DL
Richman
C M
CM
DeNardo
G L
GL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D014407:Tumor Cells, Cultured; D015431:Weight Loss; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D015021:Yttrium Radioisotopes; D017239:Paclitaxel