Annals of Oncology 10:449-453, 1999
© 1999 European Society for Medical Oncology
research-article |
Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units
1Translalional Research Laboratory, Institute for Drug Development, Cancer Therapy and Research Center San Antonio, TX
2Schering-Plough Research Institute Kenilworth NJ, USA
Correspondence to: D.D. Von Hoff, Institute for Drug Development, 14960 Omicron, San Antonio, TX 78245-3217, USA. E-mail: dvonhoff{at}saci.org
Background: The ras gene product regulates transduction of growth-proliferative signals from the membrane to the nucleus. Mutationally-activated Ras is the oncogene most frequently found in human tumors. In order to perform its function in cell signaling, Ras must be farnesylated on the CAAX motif present on the carboxyl terminus of the ras protein. This reaction is catalysed by farnesyl protein transferase. In the present study, SCH 66336, an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor, was tested against a large variety of human tumors to define its preclinical activity profile, utilizing the human tumor cloning assay.
Materials and methods: A soft agar cloning assay was used to determine the in vitro effects of SCH 66336 against primary human tumor specimens taken directly from patients. A total of 70 evaluable specimens were exposed to SCH 66336 for 14-day continuous exposure at concentrations ranging from 0.1 to 2.5 µM. In vitro responses were defined as an inhibition < 50% of human tumor colony forming units at a given concentration.
Results: There was a positive relationship between concentration and response to SCH 66336. With the highest concentration (2.5 µM), response was demonstrated in 50% (three of six) of breast tumors, 40% (6 of 15) of ovarian tumors, and 38% (5 of 13) of non-small-cell lung tumor colony forming units. Among the 69 specimens tested at the concentration of 2.5 µM, SCH 66336 had activity in 27% of tumor specimens that were resistant to doxorubicin, 38% of tumor specimens resistant to cisplatin, 33% of tumor specimens resistant to paclitaxel, and 27% of tumor specimens resistant to etoposide.
Conclusions: The broad spectrum of soft agar growth inhibition by SCH 66336 in the human tumor cloning assay, and its efficacy at physiologically relevant concentrations in animal models, suggest that SCH 66336 may deserve future clinical trials in patients with ovarian, breast and non-small-cell lung cancer.
human tumor cloning assay, farnesyltransferase inhibitor, SCH 66336
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