Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units

T. Petit, E. Izbicka, R. A. Lawrence, W. R. Bishop, Steven D Weitman, D. D. Von Hoff

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)449-453
Number of pages5
JournalAnnals of Oncology
Volume10
Issue number4
DOIs
StatePublished - 1999

Fingerprint

Farnesyltranstransferase
Stem Cells
Neoplasms
Organism Cloning
ras Proteins
Agar
lonafarnib
ras Genes
Etoposide
Growth
Transferases
Paclitaxel
Non-Small Cell Lung Carcinoma
Doxorubicin
Cisplatin

Keywords

  • Farnesyltransferase inhibitor
  • Human tumor cloning assay
  • SCH 66336

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Petit, T., Izbicka, E., Lawrence, R. A., Bishop, W. R., Weitman, S. D., & Von Hoff, D. D. (1999). Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. Annals of Oncology, 10(4), 449-453. https://doi.org/10.1023/A:1008313232381

Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. / Petit, T.; Izbicka, E.; Lawrence, R. A.; Bishop, W. R.; Weitman, Steven D; Von Hoff, D. D.

In: Annals of Oncology, Vol. 10, No. 4, 1999, p. 449-453.

Research output: Contribution to journalArticle

Petit, T, Izbicka, E, Lawrence, RA, Bishop, WR, Weitman, SD & Von Hoff, DD 1999, 'Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units', Annals of Oncology, vol. 10, no. 4, pp. 449-453. https://doi.org/10.1023/A:1008313232381
Petit, T. ; Izbicka, E. ; Lawrence, R. A. ; Bishop, W. R. ; Weitman, Steven D ; Von Hoff, D. D. / Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. In: Annals of Oncology. 1999 ; Vol. 10, No. 4. pp. 449-453.
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abstract = "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.",
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AU - Bishop, W. R.

AU - Weitman, Steven D

AU - Von Hoff, D. D.

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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.

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