REVIEW ARTICLE
Mechanisms of Drug Resistance Related to the
Microenvironment of Solid Tumors and Possible
Strategies to Inhibit Them
Qian Tan, MD, MSc,* Jasdeep K. Saggar, MSc, PhD,* Man Yu, MSc, PhD,* Marina Wang, BSc,*
and Ian F. Tannock, MD, PhD*†‡
Abstract: Drug resistance can occur at the individual cellular level or as a
result of properties of the tumor microenvironment. The convoluted vascu-
lature within tumors results in robustly proliferating well-nourished cells
located proximal to functional blood vessels and regions of slowly prolifer-
ating (often hypoxic) cells located distal to functional blood vessels. Irreg-
ular blood flow and large distances between functional blood vessels in
solid tumors lead to poor drug distribution within them such that cells distal
from functional blood vessels are exposed to ineffective concentrations of
drug, resulting in therapeutic resistance. Strategies to improve or comple-
ment the distribution of anticancer drugs within tumors hold promise for
increasing antitumor effects without corresponding increases in normal tis-
sue toxicity. In particular, use of hypoxia-targeted agents and modulation of
autophagy have shown promising results in enhancing the distribution of
drug activity within solid tumors and hence antitumor efficacy. In this re-
view, we describe causes of resistance to chemotherapy that relate to the
microenvironment of solid tumors and the potential to improve antitumor
effects by countering such mechanisms of resistance.
Key Words: Autophagy, chemotherapy, drug distribution, drug resistance,
hypoxia
(Cancer J 2015;21: 254–262)
TUMOR MICROENVIRONMENT AND
DRUG RESISTANCE
Tumor Vasculature
The tumor vasculature is a critical regulator of the delivery of
nutrients to tumor cells and of the removal of products of metab-
olism and consequently of tumor growth. Although tumor cells re-
lease factors that stimulate angiogenesis, tumor vasculature often
lacks an organized structure. As cancer cells proliferate, blood
vessels may become separated by longer distances than in normal
tissues, and raised interstitial fluid pressure (IFP) and a dense ex-
tracellular matrix may compress blood vessels and contribute to ir-
regular blood flow.1,2 Consequently, there is a limited distribution
of nutrients, including oxygen to cells located distally from func-
tional blood vessels. There may also be a buildup of cellular
breakdown products in such regions including lactic and carbonic
From the *Department of Medical Biophysics, University Health Network,
University of Toronto; †Division of Medical Oncology and Hematology, Prin-
cess Margaret Cancer Centre; and ‡University Health Network, University of
Toronto, Toronto, Ontario, Canada.
Conflicts of Interest and Source of Funding: Supported by grant KG100252
from the Komen Foundation and by grants from the Canadian Institutes of
Health Research. The authors have disclosed that they have no significant
relationships with, or financial interest in, any commercial companies
pertaining to this article.
Reprints: Ian F. Tannock, MD, PhD, and Qian Tan, MD, MSc, Princess Margaret
Cancer Centre, 9th Floor Room 417, 610 University Ave, Toronto, Ontario,
Canada M5G 2M9. E-mail: ian.tannock@uhn.ca;
susie.tan@uhnres.utoronto.ca.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1528-9117
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acids, leading to an acidic microenvironment in tumors (Fig. 1).
The abnormal vascular structure and function of solid tumors also
limit the delivery of anticancer drugs.2–4
For a systemically administered anticancer drug to kill a high
proportion of cancer cells in a solid tumor, it must cross blood ves-
sel walls and penetrate into tumor tissue. However, the distribution
of many drugs within tumors is heterogeneous, so that only a pro-
portion of the target tumor cells are exposed to a potentially lethal
concentration of the cytotoxic agent: regions distal to blood ves-
sels receive lower amounts of drug than do those cells located
proximal to tumor blood vessels. Within nutrient-deprived tumor
regions, the rate of tumor cell proliferation is relatively low,5,6
and slowly proliferating cells are resistant to most currently used
anticancer drugs, including many targeted agents. Both of these
effects contribute to the relative resistance to anticancer drugs of
cells located distal to functional blood vessels.
Tumor Hypoxia
The convoluted vasculature within tumors results in regions
where the oxygen concentration falls to zero.7 The distance from
functional blood vessels to hypoxic regions will depend on the
rate of oxygen consumption by the tumor cells but is typically at
a distance greater than 70 μm.8 Cells in chronically hypoxic re-
gions may be viable, but they are often adjacent to region of necro-
sis and are probably destined to die in the absence of treatment.
Acute hypoxia is also common in tumors and results from inter-
mittent blood flow through tumor vessels.9,10
Tumor hypoxia is an important mediator of resistance to can-
cer treatment. Cellular sensitivity to radiation depends on the gen-
eration of free radicals in the presence of oxygen, so that hypoxic
cells are relatively radioresistant. Hypoxic cells may also be resis-
tant to many anticancer drugs because (i) drugs are unlikely to be
delivered in toxic concentrations to hypoxic regions; (ii) low con-
centrations of nutrient metabolites in hypoxic regions inhibit can-
cer cell proliferation, and slowly proliferating cells are resistant to
cycle-active drugs2; (iii) tumor hypoxia is linked to loss of the p53
tumor suppressor protein that may result in loss of apoptotic abil-
ity and to increased angiogenesis and invasiveness11,12; (iv) hyp-
oxic cells can down-regulate expression of DNA topoisomerase
II, so that drugs such as doxorubicin and etoposide that target this
protein will be inefficient13; (v) hypoxia up-regulates genes in-
volved in drug resistance, including MDR genes encoding the
drug export pump P-glycoprotein14; and (vi) hypoxia can induce
autophagy, which is a survival mechanism of stressed cells.15,16
Tumor Acidity
The extracellular pH in solid tumors is often lower than in nor-
mal tissues, because of a high rate of glycolysis with production of
lactic and carbonic acids and poor clearance of these acids.17,18
Hypoxia also up-regulates the expression and activity of carbonic
anhydrase, which leads to enhanced extracellular acidification.19
The acidic extracellular environment causes basic anticancer drugs
The Cancer Journal • Volume 21, Number 4, July/August 2015
The Cancer Journal • Volume 21, Number 4, July/August 2015 Drug Resistance Related to Solid Tumors

FIGURE 1. The tumor microenvironment. Schematic representation of a functional blood vessel and its surrounding cells. Cells that are closest
to the blood vessel are richly nourished with oxygen and other nutrients and therefore proliferate rapidly. Cells that are farther away are
nutrient deprived and may become hypoxic and have an acidic microenvironment; they tend to proliferate slowly.

(such as doxorubicin) to be charged, resulting in poorer uptake into
cells because it is the uncharged form that diffuses across the
cell membrane.
The strong pH gradient between the cytoplasm of tumor cells
and acidic intracellular organelles such as endosomes and lyso-
somes20,21 may also be involved in resistance to anticancer drugs.
Many anticancer agents are weak lipophilic bases (e.g., doxorubi-
cin, mitoxantrone), and they will accumulate in acidic organelles.
When drugs are sequestered in the organelles of tumor cells, they
become less effective because less drug is available to enter the
nucleus to exert cytotoxic effects18; sequestration of drugs in these
compartments will also lead to less drug being available to diffuse
to cells more distant from functional blood vessels (Fig. 2). As
well as being sites of sequestration of basic drugs, acidic
endosomes are central to the process of autophagy, discussed be-
low as a cause of drug resistance.
We have shown that agents that raise endosomal pH might
decrease endosomal sequestration of basic anticancer drugs and

FIGURE 2. Effects of endosomal sequestration of basic drugs (nucleus [green], endosome [red/gray]). Top panel, basic anticancer drugs are
concentrated and sequestered in acidic endosomes of cells; this can limit their toxicity because less drug goes into the nucleus. Lower panel,
Agents such as chloroquine or a PPI (e.g., pantoprazole) can increase endosomal pH, thereby decreasing endosomal sequestration of basic
anticancer drugs and allowing more drugs to enter the nucleus and exert their activity, and more drugs to diffuse to distal cells.

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Tan et al
thereby modify their toxicity and tissue penetration.22 Increasing
endosomal pH might be achieved by concomitant use of other ba-
sic compounds (such as chloroquine) or by using inhibitors of the
proton pump that maintain endosomal pH at a low value (Fig. 2).
This pump is related to that which maintains acidity in the stomach
and may be inhibited by proton pump inhibitors (PPIs), which are
used clinically to reduce gastric acidity. We and others have ob-
tained evidence that PPIs may enhance the effects of chemotherapy
in animal models.23–27
Autophagy
Autophagy is a cellular mechanism used to digest old or
damaged cellular components into component residues, which
may be recycled to generate essential macromolecules. All cells
undergo autophagy, but it is up-regulated in stressed cells such
as those with nutrient or growth factor depletion and hypoxia;
such stress is common in nutrient-deprived regions of solid tu-
mors, and autophagy colocalizes with hypoxia in tumors.16,28 Au-
tophagy involves the formation of autophagosomes, which have a
double membrane enclosing cytoplasmic cellular components;
these then fuse with lysosomes to produce mature autolysosomes
in which cellular proteins are degraded by cathepsins29–31 (Fig. 3).
A series of autophagy-related proteins (known as ATGs) are
responsible for the induction and regulation of autophagy,32 and
some of them are used as markers of autophagy that can be quan-
tified in Western blots or by immunohistochemistry (IHC) applied
to tumor sections. The human form of ATG8 is microtubule-
associated protein light-chain 3B (LC3B), which exists in a cyto-
solic form as LC3B-I. Upon activation of autophagy, LC3B-I is
cleaved and modified to LC3B-II, which then binds to the mem-
brane of the autophagosome. Because of its direct association
with the autophagosome, LC3B-II has been used widely as a
marker of autophagy in mammalian models.33,34 However,
LC3B-II can undergo turnover after fusion of the lysosome,33,34
FIGURE 3. Schematic diagram of autophagy in a eukaryotic cell including the role of p62 and LC3B. Autophagy is induced by deprivation of
nutrients, hypoxia, and stress to form a membrane-contained phagophore. The second step entails sequestering of cellular breakdown
products in the double-membrane autophagosome. During this step, the LC3B protein is recruited to the auophagosome and p62 along with
the attached ubiquitin cargo attached to the LC3B protein. The fusion of a lysosome with an autophagosome generates the autolysosome.
At this step, LC3B disassociates, and p62 is degraded.
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The Cancer Journal • Volume 21, Number 4, July/August 2015
so that increase in membrane-bound LC3B-II can be due to either
increased LC3-I processing from activation of autophagy or a
buildup of membrane-bound LC3B-II following inhibition of ly-
sosomal fusion. Use of antibodies to determine activation or inhi-
bition of autophagy using LC3B isoforms is difficult if only
LC3B-II is used. An additional autophagy marker, p62/SQSTM1
(p62), is recruited with LC3B-II to autophagosomes but, unlike
LC3B-II, is degraded within the mature autolysosome.34,35 Thus,
observation of increased p62 is indicative of a buildup of the protein
because of inhibition of lysosomal fusion to the autophagosome,
that is, to inhibition of autophagy.
Autophagy is prognostic of poor outcome in multiple tu-
mor types, including cancers of the breast, lung, colon, and
melanoma.36–39 High levels of autophagy have been associated
with resistance to systemic therapy in several preclinical and
clinical models, presumably because autophagy facilitates sur-
vival of stressed or damaged cells through recycling of cellular
breakdown products.40 We have shown that treatment of cancer
cells in vitro and of solid tumors in mice with a wide variety of
anticancer agents induces autophagy, suggesting that it is a
common survival mechanism for drug-damaged cells, espe-
cially those where autophagy is already up-regulated because
of nutrient deprivation and therefore an important cause of
drug resistance.
Drug Distribution in Solid Tumors
Drugs exit blood vessels and penetrate into tissues by con-
vection and/or diffusion. Convection depends on pressure gradi-
ents between the vascular space and the interstitial space, vessel
permeability and the surface area for exchange, and the volume
and structure of the extracellular matrix; it is most important for
transport of large molecules.41 Drug diffusion is determined by
concentration gradients and by the size and charge of the mole-
cules and is the dominant mechanism for drugs of smaller
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The Cancer Journal • Volume 21, Number 4, July/August 2015
molecular weight.42 Diffusion of drugs is also limited by binding
in tissue or by their rapid metabolism once they have extravasated.
An important determinant of drug distribution within tissues is the
half-life of the drug in the circulation; drugs that have a long half-
life have a better opportunity to achieve equilibrium within the
tumor microenvironment.43
Drug distribution can be evaluated in cell culture systems
and in experimental solid tumors. In vitro multicellular mo-
dels include tumor spheroids and multilayered cell cultures
(MCCs).44–47 Spheroids develop hypoxic areas as well as cen-
tral areas of necrosis once they grow to ~500 μm in diameter.48
Drug distribution in spheroids can be studied for fluorescent
drugs or by using autoradiography to determine the distribution
of labeled drugs.49,50 Experiments using spheroids have shown
steep gradients of drug concentration from the surface for doxo-
rubicin and methotrexate.45,48 Multilayered cell cultures are
grown on collagen-coated microporous membranes: the rate
of drug penetration can be evaluated by adding a drug on one
side of the MCC and measuring its concentration on the other
as a function of time.51 This method has been used to demonstrate
slow tissue penetration of a range of clinically used chemothera-
peutic agents, including etoposide, gemcitabine, paclitaxel, and
vinblastine46,52 (Fig. 4).
Drug distribution can also be studied in animal models.
Growth of tumors in window chambers allows for direct observa-
tion of tumor microcirculation.53,54 Tumors can be excised at dif-
ferent times after drug treatment of animals bearing transplanted
tumors, including human tumor xenografts, and tissue sections
cut and processed for IHC. This analysis allows quantification
of fluorescent drugs in relation to blood vessels or regions of hyp-
oxia (defined by a marker which identifies hypoxic cells, such
as EF5 or pimonidazole), and the technique can be applied to
biopsies of human tumors.3,55 We have used this method to
quantify the distribution of the fluorescent drugs doxorubicin,
mitoxantrone, and topotecan in relation to blood vessels and
FIGURE 4. In vitro models to study drug distribution include spheroids and MCCs. The figure illustrates an MCC, which allows for a drug to be
added on one side and its concentration measured as a function of time on the other, thereby providing quantitative measurements of drug
penetration as a function of time.
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Drug Resistance Related to Solid Tumors
have shown steep gradients of decreasing drug concentration
with increasing distance from tumor blood vessels and low
penetration of drugs into hypoxic areas.56,57 For example,
doxorubicin intensity decreases to half at approximately 40 to
50 μm from the nearest blood vessels such that many viable cells
are not exposed to detectable concentrations of drug after a single
injection (Fig. 5A).
Most anticancer drugs are nonfluorescent, so their distribu-
tion within tumor tissues is difficult to assess. Fluorescently
tagged antibodies can recognize some drugs, such as the mono-
clonal antibodies cetuximab and trastuzumab; these agents have
an initial poor distribution, but equilibrium is then reached
throughout the tumor, most likely because of their long half-
lives in the circulation.58 The distribution of activity of other drugs
can be evaluated by molecular markers of drug effect, using
fluorescence-tagged antibodies that recognize cell proliferation
(Ki67), antibodies that mark cell death or apoptosis (e.g., activated
caspase 3 or 6), and markers of DNA damage such as γH2AX.59
We have validated the use of these biomarkers to study the distri-
bution of activity of anticancer agents in solid tumors and have
used quantitative IHC to demonstrate decreasing levels of activity
with increasing distance from tumor blood vessels for doxorubi-
cin, docetaxel,27,59 and paclitaxel (Figs. 5B, D).
Repopulation of Tumors Between Treatments
Repopulation of surviving cancer cells between daily frac-
tions during a course of radiotherapy has long been recognized
as a cause of resistance. Similar repopulation occurs in the longer
intervals between courses of chemotherapy; in normal tissues, this
allows recovery (e.g., of bone marrow), but in tumors, it may be a
cause of treatment failure.60,61 Our recent work has used dual la-
beling of hypoxic cells with EF5 and pimonidazole, with a vari-
able interval between applications of these markers, to determine
the fate of tumor cells that were hypoxic at the time of treatment.
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Tan et al The Cancer Journal • Volume 21, Number 4, July/August 2015

FIGURE 5. Use of IHC to quantify drug distribution in model tumors. MCF7 tumors were treated with (A) doxorubicin (25 mg/kg
intravenously) or (B and C) paclitaxel (15 mg/kg intraperitoneally) or were untreated controls. A indicates doxorubicin fluorescence intensity
as a function of distance from the nearest blood vessel in tumor sections at 10 minutes after doxorubicin injection. B and C represent
percentage of positive pixels for biomarkers as a function of distance from the nearest blood vessel in the section. B. γH2AX at 10 minutes
after paclitaxel. C, Ki67 at 24 hours after paclitaxel. D, Photomicrographs of γH2AX at 10 minutes (left panels) and Ki67 at 24 hours (right
panels) in untreated (control) and paclitaxel-treated MCF7 xenografts.

For reasons discussed previously, hypoxic tumor cells are resistant
to chemotherapy. We demonstrated that hypoxic cells that were
destined to die in the absence of treatment can survive and repop-
ulate the tumor after chemotherapy62
STRATEGIES TO IMPROVE THERAPY
Most studies of drug resistance have concentrated on the
multiple molecular causes of resistance in individual cancer
cells. Although these are important, even drug-sensitive cells
can respond to treatment only if they are exposed to an ade-
quate drug concentration. It is evident from the above that lim-
ited distribution within solid tumors limits exposure of tumor
cells to many drugs, and limited drug distribution is an impor-
tant and neglected cause of drug resistance. A variety of strate-
gies are being researched to improve or complement the limited
distribution of commonly used anticancer drugs, and these are
described in the following sections.
Improving Drug Distribution
Several strategies might lead to improved drug distribution
within solid tumors. Giving drugs by continuous infusion to main-
tain levels in blood vessels can achieve this but will also increase
delivery to normal tissues and will not necessarily improve the
therapeutic index.63 Many investigators have delivered drugs in li-
posomes or other nanoparticles, with the expectation that they
may selectively penetrate blood vessels in tumors and then release
drug over a prolonged period to increase tumor distribution,64 but
evidence for improved therapeutic effects is minimal. Any strat-
egy that leads to decreased drug uptake in cells close to blood ves-
sels will increase penetration to more distal cells; for example, we
have shown improved distribution of doxorubicin by inhibiting its
sequestration in acidic endosomes using PPIs,26 although the ef-
fect is modest and probably not the major mechanism by which
antitumor activity is increased by these agents.
High IFP may have an adverse effect on treatment because it
may cause vascular compression and inadequate drug delivery
through reduced convection. Human pancreatic tumors are ex-
tremely resistant to systemic cancer therapy, and there is evidence
that this is due to high IFP or to solid tissue stress due to elements
of the extracellular matrix preventing the delivery of drugs to
constituent cells. Reduction of IFP using hyaluronidase or of
tumor-associated stroma tissue by other agents has been reported
to improve delivery of chemotherapy in experimental models.65,66
A recent study showed that imatinib, a molecular targeting drug,
was able to reduce tumor IFP in melanoma and allowed delivery
of more doxorubicin into tumor tissue. Combined treatment
inhibited tumor growth and induced apoptosis of tumor cells.67
Inhibiting Autophagy
Agents that inhibit endosomal acidification, including (hy-
droxy)chloroquine and PPIs, can suppress autophagy, which is a
potential survival mechanism following chemotherapy, especially
for nutrient-deprived cells. An Italian group reported the use of
PPIs to sensitize cancer cells to various chemotherapeutic agents.

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The Cancer Journal • Volume 21, Number 4, July/August 2015 Drug Resistance Related to Solid Tumors

Multiple mechanisms are likely involved but appear to relate to
changes in acidity in both intracellular and extracellular compart-
ments of tumor cells. Proton pump inhibitors can inhibit autoph-
agy probably because fusion of autophagosomes with acidic
endosomes is central to the process. We have confirmed that the
PPI pantoprazole inhibits autophagy in vitro and in vivo and that
it enhances activity of docetaxel against human tumor xenografts,
with improved distribution of activity, as determined by the bio-
markers γH2AX and cleaved caspases throughout the tumors.27
We showed marked effects of docetaxel and some other anticancer
drugs to up-regulate autophagy as indicated by increased levels of
LC3B and reduced levels of p62 in all tumor regions (Fig. 6), with
opposite effects indicating inhibition of autophagy, when chemo-
therapy is combined with pantoprazole. We obtained further evi-
dence for this being the main mechanism of action by using
autophagy-deficient cells generated by shRNA knockdown of
the autophagy proteins ATG7 and BECLIN1 or both.27 Several
other studies have shown that PPIs such as omeprazole,
esomeprazole, and pantoprazole have activity against human he-
matopoietic and solid tumors; they may revert chemoresistance
in drug-resistant tumors and directly induce killing of tumor
cells.24,68,69 Our unpublished data show that a wide spectrum of
anticancer drugs up-regulate autophagy in cultured tumor cells
and that this can be inhibited by PPIs. Growing evidence suggests
that the major mechanism by which PPIs enhance the effects of
chemotherapy is by inhibition of autophagy27,70
Hypoxia-Activated Prodrugs
Hypoxia-activated prodrugs (HAPs) are administered in an
inactive form and are activated in the absence of oxygen. Hypoxic
regions within solid tumors can be identified by IHC, using
markers of hypoxia such as pimonidazole and EF5. We have
shown that the HAP, TH-302, was able to increase expression of
γH2AX and cleaved caspases in hypoxic areas of human tumor
xenografts.71 The anticancer drugs docetaxel and doxorubicin
had minimal activity in hypoxic regions, but the combination of
TH-302 and chemotherapy resulted in increased expression of
γH2AX and cleaved caspases, compared with use of either drug
alone, in regions both proximal and distal to blood vessels. Thus,
the distributions of activity of the chemotherapy drugs and of the
HAP TH-302 complement each other, although there appear to be
additional effects to enhance overall activity.62 The combination
of gemcitabine and TH-302 has given encouraging results in a
phase II trial for human pancreatic cancer,72 and a phase III trial
is in progress.
Inhibition of Tumor Cell Repopulation
Therapeutic index might be improved by inhibiting selec-
tively the repopulation of tumor cells that have the ability to regen-
erate the tumor between courses of chemotherapy, without
inhibiting repopulation of critical normal tissues. This has been
attempted in model systems using cytostatic inhibitors such as

FIGURE 6. Demonstration of the effect of drugs on the autophagy markers LC3 (indicating increased autophagy) and p62 (indicating
decreased autophagy) in different regions of PC3 human prostate cancer xenografts. Tumors treated with docetaxel (15 mg/kg
intraperitoneally), pantoprazole (200 mg/kg intraperitoneally), pantoprazole 2 hours prior to docetaxel, or untreated controls. Figures
represent percentage of positive pixels for LC3 (A, C) or p62 (B, D) as a function of distance from the nearest blood vessel (A, B) or as a
function of distance from the nearest hypoxic region (C, D). Note that docetaxel increases autophagy (increased LC3, decreased p62)
throughout the tumors and that this is inhibited by pantoprazole. *Figure adapted from Tan et al.27

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Tan et al The Cancer Journal • Volume 21, Number 4, July/August 2015

FIGURE 7. The figure demonstrates the fate of cells in prostate cancer PC3 xenografts that were initially hypoxic, as indicated by labeling with
pimonidazole, and were then exposed to a second hypoxia marker (EF5) 24 hours later. A shows the percentage of originally hypoxic cells
(pimo+) that are still present in the tumor and have reoxygenated (i.e., are pimo+, EF5−) in control tumors and in tumors at 24 hours after
treatment with docetaxel (DOC), TH-302, or the combination. Note that docetaxel alone induced the highest rate of reoxygenation and
that this is inhibited by TH-302. B indicates Ki67 staining (a marker of proliferation) in the reoxygenated cells, which is also highest after
chemotherapy and inhibited by TH-302. C indicates Ki67 staining in relation to the nearest hypoxic area and demonstrates that docetaxel
alone leads to increased Ki67 levels compared with controls and combination therapy in regions close to hypoxia. *Figure adapted from
Saggar and Tannock.62

hormonal agents in breast cancer and inhibitors of growth fac- ACKNOWLEDGMENTS

tors,73,74 but effects on outcome have been modest. As indicated
above, the poor distribution of drugs in solid tumors leads to sur-
vival of hypoxic and other poorly nourished cells, which might
then repopulate the tumor. By administering pimonidazole and
EF5 sequentially and labeling with the proliferation marker
Ki67, we have been able to follow reoxygenation and proliferation
of tumor cells that were hypoxic at the time of administration of
chemotherapy.62 We demonstrated that chemotherapy (with doxo-
rubicin or docetaxel) induced repopulation and reoxygenation of
tumor cells that were previously hypoxic. Moreover, these pro-
cesses were inhibited by the HAP TH-302, indicating another po-
tential mechanism whereby combined targeting of well-nourished
cells with chemotherapy, and hypoxic cells with HAPs, might im-
prove therapeutic effects62 (Fig. 7).
CONCLUSIONS
The effectiveness of anticancer drugs is impaired by their
limited distribution within tumors. Agents that modify or comple-
ment the activity of anticancer drugs have the ability to improve
treatment outcomes. Modification of autophagy to increase the
toxic activity of drugs within tumors and use of hypoxia-
activated prodrugs hold particular promise to improve the effec-
tiveness of conventional chemotherapy.
The authors thank all members of the Pathology Research
Program (PRP) and the Advanced Optical Microscopy Facility.
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