Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay.
OBJECTIVE
This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients.


METHODS
Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 microg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel.


RESULTS
Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 microg/ml, 11% (17/148) at 1.0 microg/ml, and 23% (33/141) at 10 microg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 microg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel.


CONCLUSIONS
MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant.
University of Texas at San Antonio and Institute for Drug Development, Cancer Therapy and Research Center, 78229, USA.
C D
CD
Britten
E
E
Izbicka
S
S
Hilsenbeck
R
R
Lawrence
K
K
Davidson
C
C
Cerna
L
L
Gomez
E K
EK
Rowinsky
S
S
Weitman
D D
DD
Von Hoff
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D000068437:Pemetrexed; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine