Successful cancer chemotherapy relies heavily on the application of various deoxynucleoside analogs. Since the very beginning of modern cancer chemotherapy, a number of antimetabolites have been introduced into the clinic and subsequently applied widely for the treatment of many malignancies, both solid tumors and hematological disorders. In the latter diseases, cytarabine has been the mainstay of treatment of acute myeloid leukemia. Although many novel compounds were synthesized in the 1980s and 1990s, no real improvement was made. However, novel technology is now capable of elucidating the molecular basis of several inborn errors as well as some specific malignancies. This has enabled the synthesis of several deoxynucleoside analogs that could be applied for specific malignancies, such as pentostatin and subsequently chlorodeoxyadenosine (cladribine) for the treatment of hairy cell leukemia. Already in the early stage of deoxynucleoside analog development, it was recognized that several of these compounds were very effective in the treatment of various viral infections, such as for the treatment of herpes infections. This formed the basis initially for the design of azidothymidine and subsequently many other analogs, which are currently successfully used for the treatment of HIV infections. As a spin-off of these research lines, some compounds not eligible for development as antiviral agents appeared to be very potent anticancer agents. The classical example is gemcitabine, now one of the most widely applied deoxynucleoside analogs, used for the (combination) treatment of non-small cell lung cancer, pancreatic cancer, bladder cancer, and ovarian cancer.
Emerging as an important new volume in the renowned Cancer Drug Discovery and Development™ series, Deoxynucleoside Analogs in Cancer Therapy expertly summarizes the current status of development and application of deoxynucleoside analogs. Authoritative up-to-date reviews are presented by scientists well known in their specific areas and all contributions include valuable sound advice on structure and topics.
Organized into several sections, the first part covers general aspects of drug uptake and metabolism and explains how novel technology has enabled a rapid expansion of this field. The second part is concerned with a number of specific drugs including cytarabine, gemcitabine, troxacitabine, clofarabine and Ara-G. The final section covers pharmacokinetics, prodrugs, and specific applications such as radiosensitization, gene therapy, and the use of deoxynucleoside analogs as tracers.
Throughout Deoxynucleoside Analogs in Cancer Therapy, the focus is on novel aspects of deoxynucleoside analogs in the clinical context, as well as on unexpected targets of these compounds, such as their specific activity against cell cycle-dependent kinases or oncogenes. The wealth of information presented here can be used to design rational combinations aimed at inhibiting various cellular signaling pathways, or combining inhibition of various targets. Deoxynucleoside Analogs in Cancer Therapy has been designed specifically to facilitate such an interaction between various fields.
Nucleoside Transport into Cells: The Role of Nucleoside Transporters SLC28 and SLC29 in Cancer Chemotherapy
Marcal Pastor-Anglada and F. Javier Casado
The Role of Deoxycytidine Kinase in DNA Synthesis and Nucleoside Analog Activation
Maria Staub and Staffan Eriksson
Deoxynucleoside Kinases and Their Potential Role in Deoxynucleoside Cytotoxicity
Birgitte Munch-Petersen and Jure Piskur
Nucleotidases and Nucleoside Analog Cytotoxicity
Sally Anne Hunsucker, Beverly S. Mitchell, and Jozef Spychala
Pumping Out Drugs: The Potential Impact of ABC Transporters on Resistance to Base, Nucleoside, and Nucleotide Analogs
Piet Borst and Peter Wielinga
Cytosine Arabinoside: Metabolism, Mechanisms, of Resistance, and Clinical Pharmacology
Isabelle Hubeek, G. J. L. Kaspers, G Ossenkoppele, and G. J. Peters
Clofarabine: Mechanisms of Action, Pharmacology, and Clinical Investigation
Varsha Gandhi and William Plunkett
L-Nucleosides as Chemotherapeutic Agents
Giuseppe Gumina, Youhoon Chong, and Chung K. Chu
Troxacitabine: A Deoxycytidine Nucleoside Analogue With Potent Antitumor Activity
Henriette Gourdeau and Jacques Jolivet
Gemcitabine: Mechanism of Action and Resistance
A. M. Bergman and G.J. Peters
Clinical Activity of Gemcitabine as a Single Agent and in Combination
J. R. Kroep, GJ Peters, and RA Nagourney
Donna S. Shewach and Theodore S. Lawrence
NONMEM Population Models of Cytosine Arabinoside and Flubaradine Phosphate in Pediatric Patients with Leukemia
Vassilios I. Avramis
The cycloSal-Nucleotide Delivery System: Development of Chemical Trojan Horses as Antiviral Agents
Chris Meier, Jan Balzarini, and Astrid Meerbach
Purine and Pyrimidine Based Analogs and Suicide GeneTherapy
3'-deoxy-3'- Fluorothymidine as a Tracer if Proliferation in Positron Emission Tomography