Summary 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.
Over the past 30 years, the National Cancer Institute has been involved in the preclinical and/or clinical evaluation of the majority of those agents approved for the treatment of cancer. Many of the new agents under consideration in the NCI program are either natural products or derivatives of natural product leads, and of critical importance to their development is the issue of drug supply. In responding to the drug supply crisis which emerged with the demonstration of the clinical efficacy of taxol, the NCI has identified several important lessons for those interested in natural product drug discovery and development. As a result, the NCI has developed plans to avert similar supply crisis in the future by initiating exploratory research projects for large-scale production of promising agents at the earliest possible point following the demonstration of confirmed antitumor activity. These plans, together with a review of the development of taxol, are presented in this paper.
Chemii iIK t mi] I s ii urn il i imIi i ire not readilv with-sized in. I large-scale production for clinical and < « »in mm r.-ial .levelo] I I the natural source. The rapidly escalating demand for taxol, mit'iiiall'. isolated from the bark of J'uxus brrri/olia, has emphasized the need for alternative sources to the wild plant, and the National Cancer Institute (NCI) has developed policies for exploring such sources at the early stages of preclinical development of potential new drugs. The potential for pharmaceutical crop development in the case of >e\eral possible anti-AIDS agents will be discussed.
Previous work in this and other laboratories has shown that penicillin is specifically and irreversibly bound by sensitive bacteria (Pasynskii and Katorskaya, 1947; Cooper and Rowley, 1949; Maass and Johnson, 1949a, 1949b; Rowley et al., 1950). It is thought that this binding is closely related to the primary mode of action of penicillin. Attempts have been made to elucidate the nature of this binding. Daniel and Johnson (1953), Cooper (1954a), and Rowley et al. (1950) have studied the effect of various factors on whole-cell uptake of penicillin in an effort to learn something of the chemical nature of the binding. Little has been learned from these studies, however. Studies have been made on cell-free extracts of untreated cells with a view toward characterizing the penicillin-binding component (Daniel and Johnson, 1953; Cooper, 1954b; Eagle, 1954). The recent discovery by Cooper (1955) that the penicillin-binding component is highly unstable indicates that isolation of this component from untreated cells will involve serious difficulties. In this work an attempt was made to isolate and identify the penicillin-cell complex from cells treated with 5s" penicillin. By this approach it was hoped to discover both the identity of the binding component and the site or sites on the penicillin molecule which may be involved in the binding. METHODS Micrococcus pyogenes var. aureus strain H was the organism used throughout this work. The procedures for growing cells in small batches, 1 Published with the approval of the Director of the Wisconsin Agricultural Experiment Station. Supported in part by a grant from the American Cancer Society upon recommendation of the Committee on Growth of the National Research Council.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.