Page 145 - Read Online

McKenna et al Hypoxia in prostate cancer

Table 1: Reported values of the partial pO 2 in human tumors and corresponding normal tissues
Tumor type n Median tumor Median % n Median Median % Fold pO 2 Reference
oxygen normal oxygen decrease a
pO 2
tissue pO 2
Brain (6) 104 13 1.7 104 26 3.4 2 [11]
Head and neck cancer 592 10 1.3 ND 5.9 4.5 [11]
(13) 30 12.2 1.6 14 40 5.3 3.3 [88]
23 14.7 1.9 30 43.8 5.8 3 [89]
65 14.6 1.9 65 51.2 6.7 3.5 [90]
Lung cancer 6 14.3 1.9 ND 5.6 3 [91]
20 16.6 2.2 42.8 5.6 2.6 [92]
Breast cancer (10) 212 10 1.3 212 52 6.8 5.2 [11,93]
Pancreatic cancer 7 2.7 0.4 7 51.6 6.8 19.1 [94]
1 2 0.3 22.7 [95]
Prostate cancer 59 2.4 0.3 59 30 3.9 12.5 b [96]
55 4.5 0.6 ND 6.7 b [97]
10 9.4 1.2 2 26.2 3.4 2.8 c [98]
Melanoma 18 11.6 1.5 20 40.5 5.3 3.5 [99]
Rectal carcinoma 14 32 4.2 52 6.8 1.6 [100]
15 19 2.5 52 6.8 2.7 [101]
Sarcoma (14) 283 14 1.8 283 51 6.7 3.6 [11]
The data in the table is adapted with permission from a review by McKeown (2014). The number of studies included for each tumor type
a
is indicated by the number in the “tumor type” column. Other data are from single studies, as referenced. Fold reduction of tumor vs.
b
normal tissue is based on all the data presented in the table (except prostate; see below); fold reduction calculated on contemporaneous
c
measurements in the psoas muscle; data from a pilot study that included values from the “normal” prostate of two bladder cancer patients.
ND: not determined; pO 2 : pressure of oxygen
instability [14] , endothelial-to-mesenchymal transition [15,16] case of the metabolically distinct anthraquinone-
and selection of cells with diminished apoptotic potential derived compounds, unidirectional HAPs (uHAPs). This
and a greater invasive potential [17,18] . These plethora review will focus on the therapeutic potential of these
of changes means that the presence of hypoxia has compounds in targeting hypoxic tumor cells, although
significant implications for cancer therapy [11,19] . Indeed, the molecular targeting of hypoxia factors such as HIF
as far back as the 1950s, it was realised that hypoxia is is an equally valid strategy for targeting hypoxia and is
an underlying cause of resistance to radiotherapy [20,21] . reviewed elsewhere [30,33] .
Since then it has been consistently shown that high
levels of hypoxia significantly correlate with increasing The concept underpinning the use of HAPs is well-
clinical stage and can predict biochemical failure established and several recent reviews exist, which we
following radiotherapy [22] . Recent studies have shown refer to for further understanding [32,33] . When oxygen
that hypoxic conditions significantly enhances exosome levels are very low HAPs or uHAPs are reduced to
secretion in a HIF-1α-dependent way [23] . Exosomes are covalently-binding active cytotoxins or release DNA-
microvesicles containing a cargo of signature proteins, damaging radicals [31,32] . Thus the incorporation of
lipids, nucleic acid and metabolites that can contribute a HAP into a treatment regime should be an ideal
to the remodelling of the tissue microenvironment [24,25] . approach to specifically target tumor cells, particularly
In prostate cancer models they have been shown to as hypoxia is rare in normal tissues [34] . Other
mediate angiogenesis, cell stemness and activation properties for an effective HAP, discussed throughout
of the surrounding tumor stroma [26] . Similarly, this review, include (1) the ability to reach hypoxic
hypoxia has been linked with increased resistance cells, (2) pharmacological features which allow it to be
to chemotherapeutic drugs [27,28] . Therefore, hypoxia metabolised effectively, and (3) exertion of a lasting,
is clearly a significant obstacle to the effective targeted effect on the tumor [32] . With these in mind
treatment of tumors, so it is a viable therapeutic several compounds have been developed and tested
strategy to directly target hypoxic tumor cells in an in vitro, in vivo and in patients with different cancers
attempt to improve treatment [27,29,30] . Although such a [Table 2 and Figure 2].
strategy has yet to establish clinical acceptance, one
of the most promising translational approaches for However, although encouraging results have been
patient treatment is based on the use of bioreductive obtained from preclinical studies many of the HAPs
drugs [31,32] . These are now more commonly known listed in Table 2 have not been realised in clinical trials.
as hypoxia activated prodrugs (HAPs) or, in the Currently, only a few of these molecules are being
Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ March 1, 2018 3