Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials (original) (raw)

Abstract

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10–7.5 M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10–4 M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity. © 2001 Cancer Research Campaign www.bjcancer.com

Keywords: anticancer drug discovery, in vitro-to-in vivo correlations, clinical trials

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Selected References

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  1. Alley M. C., Scudiero D. A., Monks A., Hursey M. L., Czerwinski M. J., Fine D. L., Abbott B. J., Mayo J. G., Shoemaker R. H., Boyd M. R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988 Feb 1;48(3):589–601. [PubMed] [Google Scholar]
  2. Ghose A. K., Viswanadhan V. N., Wendoloski J. J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999 Jan;1(1):55–68. doi: 10.1021/cc9800071. [DOI] [PubMed] [Google Scholar]
  3. Hahnfeldt P., Panigrahy D., Folkman J., Hlatky L. Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res. 1999 Oct 1;59(19):4770–4775. [PubMed] [Google Scholar]
  4. History of the Cancer Chemotherapy Program. Cancer Chemother Rep. 1966 Oct;50(7):349–396. [PubMed] [Google Scholar]
  5. Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K., Vistica D., Hose C., Langley J., Cronise P., Vaigro-Wolff A. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991 Jun 5;83(11):757–766. doi: 10.1093/jnci/83.11.757. [DOI] [PubMed] [Google Scholar]
  6. Paull K. D., Shoemaker R. H., Hodes L., Monks A., Scudiero D. A., Rubinstein L., Plowman J., Boyd M. R. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst. 1989 Jul 19;81(14):1088–1092. doi: 10.1093/jnci/81.14.1088. [DOI] [PubMed] [Google Scholar]
  7. Phillips R. M., Pearce J., Loadman P. M., Bibby M. C., Cooper P. A., Swaine D. J., Double J. A. Angiogenesis in the hollow fiber tumor model influences drug delivery to tumor cells: implications for anticancer drug screening programs. Cancer Res. 1998 Dec 1;58(23):5263–5266. [PubMed] [Google Scholar]
  8. Sausville E. A., Feigal E. Evolving approaches to cancer drug discovery and development at the National Cancer Institute, USA. Ann Oncol. 1999 Nov;10(11):1287–1291. doi: 10.1023/a:1008333901925. [DOI] [PubMed] [Google Scholar]
  9. Scholz C. C., Berger D. P., Winterhalter B. R., Henss H., Fiebig H. H. Correlation of drug response in patients and in the clonogenic assay with solid human tumour xenografts. Eur J Cancer. 1990;26(8):901–905. doi: 10.1016/0277-5379(90)90196-z. [DOI] [PubMed] [Google Scholar]
  10. Venditti J. M. Preclinical drug development: rationale and methods. Semin Oncol. 1981 Dec;8(4):349–361. [PubMed] [Google Scholar]
  11. Venditti J. M., Wesley R. A., Plowman J. Current NCI preclinical antitumor screening in vivo: results of tumor panel screening, 1976-1982, and future directions. Adv Pharmacol Chemother. 1984;20:1–20. doi: 10.1016/s1054-3589(08)60263-x. [DOI] [PubMed] [Google Scholar]