Abstract
Tricyclic nucleoside 5′-phosphate (TCN-P) was evaluated in two models of human ovarian cancer. TCN-P reduced both colony number and volume in clonogenic assays employing human ovarian cancer cell lines. TCN-P cytotoxicity depended on the concentration, exposure duration and cell line studied, but not on cell line plating efficiency or growth rate in soft agarose. Comparison of experimental IC50 concentrations for 1 hour or continuous TCN-P exposure with reported clinically relevant concentrations suggests that therapeutic TCN-P levels are more likely to be achieved by continuous infusions. Cell lines and sublines with resistance to several standard chemotherapeutic agents acquired both in vivo and in vitro were at most 2.6-fold cross-resistant to TCN-P with 1 hour drug exposure. Cross-resistance was not evident with continuous TCN-P exposure. Intermittent bolus TCN-P (100 mg/kg/d × 5) was ineffective in an in vivo xenograft model of human ovarian cancer. These data suggest that TCN-P is most likely to be clinically effective against ovarian cancer, and may be non-cross-resistant with several standard agents, if administered by continuous infusion. Preclinical evaluation of new agents, such as TCN-P, in these experimental models may provide information useful in subsequent clinical trials.
Similar content being viewed by others
Abbreviations
- CRI:
-
cross-resistance index
- EGF:
-
epidermal growth factor
- IC50 :
-
drug concentration causing 50% inhibition of colony formation
- LD10 :
-
lethal dose in 10% of animals
- NS:
-
normal saline
- r:
-
correlation coefficient
- RCV:
-
relative colony volume
- RPMI:
-
Roswell Park Memorial Institute
- SF:
-
surviving fraction
- TCN:
-
tricyclic nucleoside
- TCN-P:
-
tricyclic nucleoside 5′-phosphate
References
Cancer Therapy Evaluation Program, Clinical Brochure, Tricyclic Nucleoside 5′-phosphate (TCN-P) NSC 280594, Investigational Drug Branch, National Cancer Institute, Bethesda, MD, June 1981 (revised January 1982)
Bennett LL Jr, Smithers D, Hill DL, Rose LM, Alexander JA: Biochemical properties of the nucleoside of 3-amino-1,5-dihydro-5-methyl-1,4,5,6,8-pentaazaacenaphthylene (NSC-154020). Biochem Pharmacol 27:233–241, 1978
Basseches PJ, Durski A, Powis G: High performance liquid Chromatographic assay of the antineoplastic agent tricyclic nucleoside 5′-phosphate and its disposition in rabbit. J Chromato 233:227–234, 1982
Wotring LL, Townsend LB, Crabtree GW, Parks RE Jr: A possible role for ecto-5′-nucleotidase in cytotoxicity and intracellular nucleotide formation from the tricyclic nucleoside-5′-phosphate (TCN-P).(Abstract) Proc Am Assoc Cancer Res 22:257, 1981
Plagemann PGW: Transport, phosphorylation, and toxiciy of a tricyclic nucleoside in cultured Novikoff rat hepatoma cells and other cell lines and release of its monophosphate by the cells. J Natl Cancer Inst 57:1283–1295, 1976
Cobb WR, Bogden AE, Reich SD, Griffin TW, Kelton DE, LePage DJ: Activity of two Phase I drugs, homoharringtonine and tricyclic nucleotide, against surgical explants of human tumors in the 6-day subrenal capsule assay. Cancer Treat Rep 67:173–178, 1983
Canetta RM, Carter SK: Developing new drugs for ovarian cancer: a challenging task in a changing reality. J Cancer Res Clin Oncol 107:111–124, 1984
Stanhope CR, Smith JP, Rutledge F: Second trial drugs in ovarian cancer. Gynecol Oncol 5:52–58, 1977
Ozols RF, Young RC: Chemotherapy of ovarian cancer. Semin Oncol 11:251–263, 1984
Venditti JM: Preclinical drug development: rationale and methods. Semin Oncol 8:349–361, 1981
Behrens BC, Louie KG, Hamilton TC, Curt G, Kinsella T, Young RC, Ozols RF: Resistance (R) and cross-resistance (XR) of human ovarian cancer (OC) cell lines to Adriamycin (AD), melphalan (ME) and irradiation (XRT). (Abstract) Proc Am Assoc Cancer Res 25:336, 1984
Behrens BC, Grotzinger KR, Hamilton TC, Whang-Peng J, Batist G, Louie KG, Knutsen T, Tsuruo T, McKoy WM, Young RC, Ozols RF: Cytotoxicity of 3 cisplatin (CP) analogues (CPAs) in a drug-sensitive and new CP-resistant human ovarian cancer (OC) cell line. (Abstract) Proc Am Assoc Cancer Res 26:262, 1985
Louie KG, Behrens BC, Kinsella TJ, Hamilton TC, Grotzinger KR, McKoy WM, Winkler MA, Young RC, Ozols RF: Radiation survival parameters of antineoplastic drugsensitive and -resistant human ovarian cancer cell lines and their modification by buthionine sulfoximine. Cancer Res: 45:2110–2115, 1985
Hamilton TC, Young RC, Ozols RF: Experimental model systems of ovarian cancer: applications to the design and evaluation of new treatment approaches. Semin Oncol 11:285–298, 1984
Hamilton TC, Young RC, Louie KG, Behrens BC, McKoy WM, Grotzinger KR, Ozols RF: Characterization of a xenograft model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. Cancer Res 44:5286–5290, 1984
Salmon SE, Young L, Lebowitz J, Thompson S, Einsphar J: Evaluation of the Omincon Image Analysis System for counting humour tumor colonies. In: Salmon SE and Trent JM (eds): Human Tumor Cloning, Grune and Stratton, NewYork, 1984, pp. 163–171
Armitage P: Statistical Methods in Medical Research. Oxford: Blackwell Scientific Publications, 1971
Dickie BC, Rao GN, Thompson GW, Boysen BG, Glaza SM: Preclinical toxicity study of pentaazaacenaphthylene5′ phosphate ester (NSC-280594) in CD2F1 mice and beagle dogs. (Abstract) Proc Am Assoc Cancer Res 24:296, 1983
Crabtree GW, Spremulli EN, Wiemann MC, Smith DE, Salvatore JR, Cummings FJ, Calabresi P: Phase I clinical and pharmacokinetic study of tricyclic nucleoside-5′-monophosphate (TCN-P; NSC 280594). (Abstract) Proc Am Soc Clin Oncol 2:33, 1983
Schilcher R, Haas C, Young J, Baker L: Phase I evaluation and pharmacokinetics of tricyclic nucleoside 5′-phosphate (TCN-P, NSC 280594) in a weekly I.V. schedule. (Abstract) Proc Am Soc Clin Oncol 2:31, 1983
Zhengang G, Savaraj N, Lu K, Feun LG, Burgess MA, Benjamin RS, Loo TL: Tissue and tumor penetration of 3-amino-1,5-dihydro-5-methyI-1-D-ribofuranosyl-1,4,5,6, 8-pentaazaacenaphthylene 5′ monophosphate (TCN-P, NSC 280594) in man. (Abstract) Proc Am Soc Clin Oncol 2:41, 1983
Moon TE, Rodney SR, Thompson SP, Meyskens Jr FL: Modifying survival fraction (SF) to better reflect drug effect on clonogenic cell proliferation. (Abstract) Proc Am Assoc Cancer Res 25:374, 1984
Bertoncello I, Bradley TR, Campbell JJ, Day AJ, McDonald IA, McLeish GR, Quinn MA, Rome R, Hodgson GS: Limitations of the clonal agar assay for the assessment of primary human ovarian tumor biopsies. Br J Cancer 45:803–811, 1982
Roshon S, Natale R, Gau T, Wotring L, Townsend L, Koller C: In vitro activity of tricyclic nucleoside 5′-phosphate (TCN-P) assayed by the human tumor cloning assay (HTCA). (Abstract) Proc Am Assoc Cancer Res 24:317, 1983
Louie KG, Hamilton TC, Winker MA, Behrens BC, Tsuruo T, Klecker Jr RW, McKoy WM, Grotzinger KR, Myers CE, Young RC, Ozols RF: Adriamycin accumulation and metabolism in adriamycin-sensitive and -resistant human ovarian cancer cell lines. Biochem Pharmacol, in press, 1985
Feun LG, Savaraj N, Bodey GP, Lu K, Yap BS, Ajani JA, Burgess MA, Benjamin RS, McKelvey E, Krakoff I: Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule. Cancer Res 44:3608–3612, 1984
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Behrens, B.C., Hamilton, T.C., Louie, K.G. et al. Activity of tricyclic nucleoside 5′-phosphate in model systems of human ovarian cancer. Invest New Drugs 4, 295–304 (1986). https://doi.org/10.1007/BF00173502
Issue Date:
DOI: https://doi.org/10.1007/BF00173502