Abstract
The major goal of modern anticancer drug discovery is to produce innovative agents that are both well tolerated and at the same time exhibit a step jump in effectiveness against the major solid tumours. In order to maximize the benefit to patients novel drug candidates must be discovered and developed rapidly and efficiently. State of the art scientific techniques together with up to date process and resource management methods are essential and particular attention should be focused on bottlenecks which occur on the critical path. Significant issues are frequently encountered in the areas of in vivo pharmacokinetics and pharmacodynamics. Techniques such as PET have the potential to add value to the drug development process by allowing the measurement of drug uptake and clearance kinetics, including spatial heterogeneity variables, within tumour and normal tissues rather than the usual plasma measurements. This is an area that is very neglected currently. Even more important is the potential to obtain information on the pharmacodynamics of drug action in the tissues, including for example effects on DNA synthesis. Both pharmacokinetic and pharmacodynamic properties can potentially be quantified within the context of measured biochemical and physiological variables such as blood flow, oxygen utilization, receptor expression and occupancy, and so on. Timely indicators of pharmacological effectiveness during early clinical trials are seen as major milestones.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Schwartsmann G and Workman P. Anticancer drug discovery in the 1990s: A European perspective. Eur J Cancer 1993; 29A: 3–14.
Grever R, Schepartz SA and Chabner BA. The National Cancer Institute: Cancer Drug Discovery and Development Program. Semin Oncol 1992; 19: 622–628.
Workman P. The potential of molecular oncology to define new drug targets. In: Kerr DR and Workman P. New Molecular Targets for Cancer Chemotherapy. Boca Raton: CRC Press, 1994: 1–29.
Brunton VG and Workman P. Cell-signalling targets for antitumour drug development. Cancer Chemother Pharmacol 1993; 32: 1–19.
Powis G and Workman P. Signalling targets for the development of cancer drugs. Anti-Cancer Drug Design 1994; 9: 263–277.
Gianni L, McVie JG and Workman P. The relevance of pharmacology in clinical oncology practice. Annal Oncol 1993; 4: 463–469.
Workman P and Graham MA. Pharmacokinetics and cancer chemotherapy. Eur J Cancer 1994; 39A: 706–710.
Workman P and Graham MA, editors. Pharmacokinetics and cancer chemotherapy. Cancer Surveys. Volume 17. New York: Cold Spring Harbor Laboratory Press, 1993.
Newell DR. Can pharmacokinetic and pharmacodynamic studies improve cancer chemotherapy. Annal Oncol 1994; 5 (Suppl 4): S9–S15.
Maxwell RJ. New techniques in pharmacokinetic analysis III. Nuclear Magnetic Resonance. In: Workman P and Graham MA, editors. Pharmacokinetics and Cancer Chemotherapy. Cancer Surveys. Volume 17. New York: Cold Spring Harbor Laboratory Press, 1993: 415–423.
Tilsey DWO, Harte RJA, Jones T et al. New techniques in pharmacokinetic analysis of cancer drugs. IV Positron emission tomography. In Workman P and Graham MA, editors. Pharmacokinetics and Cancer Chemotherapy. Cancer Surveys. Volume 17. New York: Cold Spring Harbor Laboratory Press, 1993: 425–442.
Workman P and Stratford IJ. The experimental development of bioreductive drugs and their role in cancer therapy. Cancer Metast Rev 1993; 12: 73–82.
Rampling R, Cruickshank G, Lewis AD, Fitzsimmons SA and Workman P. Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumours. Int J Radiat Oncol Biol Phys 1994; 29: 427–431.
Koh WJ, Rasey JS, Evans ML et al. Imaging of hypoxia in tumors with fluorine-18 fluoromisonidazole. Int J Radiat Oncol Biol Phys 1992; 22; 199–212.
Maxwell RJ, Workman P and Griffiths JR. Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by 19F magnetic resonance spectroscopy in vivo. Int J Radiat Oncol Biol Phys 1989; 16: 925–929.
Raleigh JA, Franko AJ, Kelly DA, Trimble LA Andersen PS. Development of an in vivo 19F magnetic resonance method for measuring oxygen deficiency in tumors. Magnet Res Med 1991; 22: 451–466.
Aboagye EO, McCoy CL, Maxwell RJ et al. Assessment of tumour hypoxia by quantitative 19F magnetic resonance spectroscopy. Proceedings of the Society of Magnetic Resonance, 1994; 1394.
Workman P and Walton MI. Enzyme-directed bioreductive drug development. In: Adams GE, Breccia A, Fielden EM and Wardman P, editors. Selective activation of drugs by redox processes. New York: Plenum Press, 1990: 173–191.
Workman P. Enzyme-directed bioreductive drug development revisited: A commentary on recent progress and future prospects with emphasis on quinone anticancers and quinone metabolizing enzymes. Oncol Res in press.
Walton MI, Bibby MC, Double JA, Plumb JA and Workman P. DT-diaphorase correlates with sensitivity to the indoloquinone EO9 in mouse and human colon carcinomas. Eur J Cancer 1992; 28A: 1597–1600.
Robertson N, Haigh A, Adams GE and Stratford IJ. Factors affecting the sensitivity to EO9 in rodent and human tumour cells in vitro: DT-diaphorase and hypoxia. Eur J Cancer 1994; 30A: 1013–1019.
Ross D, Siegel D, Beall H, Prakash AS, Mulcahy RT and Gibson NW. DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C. Cancer Metast Rev 1993; 12; 83–101.
Workman P, Brunton VG and Robins DJ. Tyrosine kinase inhibitors. Semin Cancer Biol 1992; 3: 369–381.
Workman P, Brunton VG and Robins DJ. Discovery and design of tyrosine kinase inhibitors. In: Workman P, editor. New approaches in cancer pharmacology: Drug design and development, Volume II, ESO Monograph. Berlin: Springer-Verlag, 1994: 55–70.
Gibbs JB and Oliff A. Pharmaceutical research in molecular oncology. Cell 1994; 79: 193–198.
Gibbs JB, Oliff A and Kohl NE. Farnesyl transferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 1994; 77: 175–178.
Hartwell LH and Kastan MB. Cell cycle control and Cancer. Science 1994; 266: 1821–1828.
Karp JE and Broder S. New directions in molecular medicine. Cancer Res 1994; 54: 653–665.
Culver KW and Blaese RM. Gene therapy for cancer. Trends in Genetics 1994; 10: 174–178.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Workman, P. (1995). Bottlenecks in Anticancer Drug Discovery and Development: In vivo Pharmacokinetic and Pharmacodynamic Issues and the Potential Role of PET. In: Comar, D. (eds) PET for Drug Development and Evaluation. Developments in Nuclear Medicine, vol 26. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-0429-6_26
Download citation
DOI: https://doi.org/10.1007/978-94-011-0429-6_26
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-010-4191-1
Online ISBN: 978-94-011-0429-6
eBook Packages: Springer Book Archive