Drug penetration in solid tumours

Andrew I Minchinton1, Ian F Tannock

  • 1Department of Medical Biophysics, British Columbia Cancer Research Centre, Vancouver, Canada. aim@bccrc.ca

Insights

Effective chemotherapy requires anticancer drugs to reach all cancer cells. This study highlights neglected issues of poor drug distribution in tumors and proposes strategies to improve drug penetration for better cancer treatment outcomes.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Research

Background:

  • Chemotherapy effectiveness relies on efficient drug delivery to all cancer cells.
  • Limited drug distribution within tumors is a neglected factor in cancer treatment resistance.
  • Molecular mechanisms of resistance have been prioritized over drug penetration studies.

Purpose of the Study:

  • To review evidence on incomplete anticancer drug distribution in tumor tissues.
  • To propose strategies for enhancing drug penetration in tumors.
  • To suggest selecting compounds based on tissue penetration abilities to improve therapeutic index.

Main Methods:

  • Literature review and evidence synthesis on drug distribution in tumors.
  • Analysis of factors affecting drug penetration in neoplastic tissues.
  • Exploration of strategies to overcome drug distribution challenges.

Main Results:

  • Evidence indicates that the distribution of many anticancer drugs within tumor tissue is often incomplete.
  • Poor drug penetration can limit the efficacy of chemotherapy.
  • Strategies to improve drug penetration may enhance therapeutic outcomes.

Conclusions:

  • Improving drug penetration in tumors is crucial for effective chemotherapy.
  • Developing strategies to enhance drug distribution can overcome treatment resistance.
  • Selecting drugs based on penetration capabilities can increase the therapeutic index and improve patient outcomes.

Related Concept Videos

Drug Absorption: Overview01:17

Drug Absorption: Overview

The process of drug absorption signifies the transition of a drug from its site of administration into the plasma. This process is influenced by various factors, including the route of administration, the anatomy of the absorption site, the mechanism of absorption, gut motility, and the drug's physicochemical properties.
When drugs are injected intravenously, they directly enter the systemic circulation. Alternatively, orally administered drugs navigate through the gastrointestinal (GI) tract.
Cellular Membranes and Drug Transport01:24

Cellular Membranes and Drug Transport

Drugs must traverse multiple biological barriers, such as multi-layered skin, single-layered intestinal epithelium, and the plasma membrane, to reach their target sites within the body. The plasma membrane, a highly structured composite of phospholipids, carbohydrates, and proteins, is the cell's protective boundary, facilitating selective substance exchange.
Phospholipids arrange themselves into a bilayer, with hydrophilic heads oriented outward and hydrophobic tails facing inward.
Mechanisms of Drug Absorption: Paracellular, Transcellular, and Vesicular Transport01:23

Mechanisms of Drug Absorption: Paracellular, Transcellular, and Vesicular Transport

Drugs need to permeate cell membranes to reach their target sites after administration. Orally administered drugs must transcend intestinal epithelial membrane barriers to infiltrate the systemic circulation. Drugs with a molecular weight of less than 500 Daltons diffuse through gaps between neighboring cells, called paracellular pathways.
However, most drugs use the transcellular route, traversing directly through the cell membranes via two mechanisms: passive and active transport. Passive...
Carrier-Mediated Transport01:06

Carrier-Mediated Transport

Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Methods for Studying Drug Absorption: In situ01:09

Methods for Studying Drug Absorption: In situ

In situ experiments, such as the Doluisio method and Single-Pass Perfusion technique, provide critical insights into drug uptake by simulating in vivo conditions for drug absorption.
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...
Bioavailability Enhancement: Drug Permeability Enhancement01:27

Bioavailability Enhancement: Drug Permeability Enhancement

After oral administration, poor permeability often limits the rate at which drugs are absorbed through the intestinal epithelium. Enhancing drug permeability is crucial for effective therapy, and several strategies have been developed to overcome this challenge.One effective strategy involves the use of lipid-based formulations. These formulations enhance dissolution and solubility, targeting physiological mechanisms to increase drug absorption. This includes stimulating bile salt secretion,...