Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jun 10:3:154.
doi: 10.3389/fonc.2013.00154. eCollection 2013.

The tumor microenvironment and strategies to improve drug distribution

Jasdeep K Saggar  1 , Man Yu, Qian Tan, Ian F Tannock
Affiliations

The tumor microenvironment and strategies to improve drug distribution

Jasdeep K Saggar et al. Front Oncol. .

Abstract

The microenvironment within tumors is composed of a heterogeneous mixture of cells with varying levels of nutrients and oxygen. Differences in oxygen content result in survival or compensatory mechanisms within tumors that may favor a more malignant or lethal phenotype. Cells that are rapidly proliferating are richly nourished and preferentially located close to blood vessels. Chemotherapy can target and kill cells that are adjacent to the vasculature, while cells that reside farther away are often not exposed to adequate amounts of drug and may survive and repopulate following treatment. The characteristics of the tumor microenvironment can be manipulated in order to design more effective therapies. In this review, we describe important features of the tumor microenvironment and discuss strategies whereby drug distribution and activity may be improved.

Keywords: drug distribution; drug penetration; hypoxia-activated pro-drugs; pharmacodynamic markers; solid tumor; tumor microenvironment.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(A) Strategies to overcome limited drug distribution in solid tumors. Solid tumors are featured by irregular and poorly organized vasculature. This makes blood-borne oxygen and nutrients difficult to reach tumors cells distant from vessels and eventually leads to formation of regions with low oxygen (hypoxia) and nutrient concentrations. In these areas, tumor cells are usually highly resistant to chemotherapy and radiation therapy. Drug distribution in solid tumors is influenced by many factors, such as physicochemical properties of drugs, consumption of drugs by cells proximal to blood vessels, and the volume and organization of the extracellular matrix (ECM). Strategies to enhance drug distribution in tumors (indicated by yellow background and dashed lines) include increase of tumor blood flow, decrease of high interstitial fluid pressure (IFP), and modification of ECM. Combination treatment using “conventional” therapeutics together with drugs (e.g., hypoxia-activated pro-drugs and agents targeting autophagy) that are able to specifically target cells distant from vasculature also have potential to improve therapeutic efficacy. (B) Schematic representation of multilayered cell cultures (MCCs) to quantify drug penetration. A drug is first added into the small compartment above the MCC. After its passage from the semi-liquid media through the MCC, drug is sampled from the receiving compartment below the MCC and measured.
Figure 2
Figure 2
Prostate cancer PC-3 xenografts (A) untreated control or (B) treated with docetaxel (15 mg/kg). (A,B) Show changes in γH2aX (in cyan), a biomarker of drug effect, in relation to tumor blood vessels (in red) at 10 min after injection. (C) Represents quantitative analysis of the distribution of γH2aX-positive cells in relation to the nearest blood vessel in tumors treated with docetaxel for 10 min (green line) and untreated controls (blue line). Points indicate average of six mice per group; bars, SE. ♢: control; ∘: docetaxel.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Borad M. J., Reddy S., Bahary N., Uronis H., Sigal D. S., Cohn A. L., et al. (2012). Randomized Phase II Study of the Efficacy and Safety of Gemcitabine + TH-302 (G+T) vs Gemcitabine (G) Alone in Previously Untreated Patients with Advanced Pancreatic Cancer. Chicago, IL: American Association of Cancer Research
    1. Conger A. D., Ziskin M. C. (1983). Growth of mammalian multicellular tumor spheroids. Cancer Res. 43, 556–560 - PubMed
    1. De Milito A., Canese R., Marino M. L., Borghi M., Iero M., Villa A., et al. (2010). pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int. J. Cancer 127, 207–219 10.1002/ijc.25009 - DOI - PubMed
    1. De Milito A., Iessi E., Logozzi M., Lozupone F., Spada M., Marino M. L., et al. (2007). Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res. 67, 5408–5417 10.1158/0008-5472.CAN-06-4095 - DOI - PubMed
    1. Denny W. A. (2010). Hypoxia-activated prodrugs in cancer therapy: progress to the clinic. Future Oncol. 6, 419–428 10.2217/fon.10.1 - DOI - PubMed