TY - JOUR
T1 - Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units
AU - Petit, T.
AU - Izbicka, E.
AU - Lawrence, R. A.
AU - Bishop, W. R.
AU - Weitman, S.
AU - Von Hoff, D. D.
N1 - Funding Information:
T. Petit is the recipient of a Federation Nationale des Centres de Lutte Contre le Cancer (France) grant and a travel bursury award by the Societe Francaise du Cancer.
PY - 1999
Y1 - 1999
N2 - 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 vivo 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.
AB - 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 vivo 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.
KW - Farnesyltransferase inhibitor
KW - Human tumor cloning assay
KW - SCH 66336
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U2 - 10.1023/A:1008313232381
DO - 10.1023/A:1008313232381
M3 - Article
C2 - 10370788
AN - SCOPUS:0032932257
VL - 10
SP - 449
EP - 453
JO - Annals of Oncology
JF - Annals of Oncology
SN - 0923-7534
IS - 4
ER -