Pharmacokinetic strategies to improve drug penetration and entrapment within solid tumors.
Despite the discovery of a large number of anticancer agents, cancer still remains among the leading causes of death since the middle of the twentieth century. Solid tumors possess a high degree of genetic instability and emergence of treatment resistance. Tumor resistance has emerged for almost all approved anticancer drugs and will most probably emerge for newly discovered anticancer agents as well. The use of pharmacokinetic approaches to increase anticancer drug concentrations within the solid tumor compartment and prolong its entrapment might diminish the possibility of resistance emergence at the molecular pharmacodynamic level and might even reverse tumor resistance. Several novel treatment modalities such as metronomic therapy, angiogenesis inhibitors, vascular disrupting agents and tumor priming have been introduced to improve solid tumor treatment outcomes. In the current review we will discuss the pharmacokinetic aspect of these treatment modalities in addition to other older treatment modalities, such as extracellular matrix dissolving agents, extracellular matrix synthesis inhibitors, chemoembolization and cellular efflux pump inhibition. Many of these strategies showed variable degrees of success/failure; however, reallocating these modalities based on their influence on the intratumoral pharmacokinetics might improve their understanding and treatment outcomes.
Department of Pharmacology, Medical Division, National Research Centre, Dokki, Giza, Egypt; Center for Pharmaceutical Biotechnology and Nanomedicine (CPBN), Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA; Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Ahmed M
AM
Al-Abd
Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Zekra K
ZK
Aljehani
Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Rana W
RW
Gazzaz
Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Sarah H
SH
Fakhri
Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Aisha H
AH
Jabbad
Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Abdulrahman M
AM
Alahdal
Center for Pharmaceutical Biotechnology and Nanomedicine (CPBN), Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Electronic address: v.torchilin@neu.edu.
Vladimir P
VP
Torchilin
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016461:Chemoembolization, Therapeutic; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects
D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins
Angiogenesis inhibitors; Chemoembolization; Extracellular matrix dissolving agents; Intratumoral pharmacokinetics; Metronomic therapy; P-glycoprotein inhibitors; Tumor priming; Vascular disrupting agent