Does paclitaxel (Taxol) given after (111)In-labeled monoclonal antibodies increase tumor-cumulated activity in epithelial cancers?
OBJECTIVE
Paclitaxel synergized radiolabeled monoclonal antibodies, enhancing therapeutic effect in studies in mice with human xenografts. Paclitaxel was also observed to increase tumor uptake in imaging studies of (111)In-DOTA-Gly3Phe-m170 in patients with breast and prostate cancers. Further evaluations of tissue-cumulated activities, therapeutic indices, and pharmacokinetics were done using data for patients with breast and prostate cancer and for mice with human breast cancer xenografts.


METHODS
In radioimmunotherapy trials, 12 patients with breast or prostate cancer were given two imaging doses (5 mCi each) of (111)In-DOTA-Gly3Phe-m170 1 week apart. Five of these patients were given a single dose of paclitaxel i.v. (75 mg/m2) 2 days after the second dose of (111)In. In a subsequent study, athymic mice with human breast cancer xenografts were given (111)In-DOTA-Gly3Phe-ChL6 alone, or in combination with daily paclitaxel i.p. (300 microg) one or more times. Pharmacokinetics were studied for at least 6 days in patients and 5 days in mice. Cumulated activities were determined for tumors and normal tissues.


RESULTS
Tumor-cumulated activity for every patient in the paclitaxel-treated group increased for the second dose of (111)In-DOTA-Gly3Phe-m170. The median ratio of cumulated activities in tumors for imaging dose 2 to those for dose 1 was 1.0 (0.8-1.3) in patients that were not given paclitaxel and 1.3 (1.2-1.4) in patients given paclitaxel. Normal tissue-cumulated activities were not different for the two doses. Mice given paclitaxel 1 day after (111)In-DOTA-Gly3Phe-ChL6 also showed an increase in tumor-cumulated activity, 22.9 (+/- 1.3) versus 19.4 (+/- 3.3) microCi h/g/microCi (P = 0.05). Cumulated activities of normal tissues were similar for all groups of mice.


CONCLUSIONS
Paclitaxel given 1 to 2 days after (111)In-DOTA-Gly3Phe-monoclonal antibody increased the tumor-cumulated activity in patients and in mice with epithelial cancers and did not alter cumulated activities in normal tissues.
Miers
Laird
L
School of Medicine, University of California Davis, Davis, California, USA.
Lamborn
Kathleen
K
Yuan
Aina
A
Richman
Carol
C
Natarajan
Arutselvan
A
DeNardo
Sally
S
DeNardo
Gerald
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D006573:Heterocyclic Compounds, 1-Ring; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D017239:Paclitaxel