Success of Cancer Chemotherapy
Appears Enhanced by Blood Pressure Drug
Treatment with losartan increases
drug delivery in animal models by opening collapsed tumor blood vessels
in breast and pancreatic cancer
Before treatment with the angiotensin inhibitor losartan,
stresses within a tumor caused by the buildup of collagen (blue)
compress blood vessels and restrict blood flow (green).
Bottom image: After losartan treatment, blood vessels open
up, restoring the blood flow required for effective
chemotherapy. (Vikash Chauhan, PhD, Steele Lab for Tumor
Biology, Massachusetts General Hospital)
Oct. 2, 2013 - Use of existing,
well-established hypertension drugs could improve the outcome of cancer
chemotherapy by opening up collapsed blood vessels in solid tumors.
Massachusetts General Hospital (MGH) investigators report the
angiotensin inhibitor losartan improved the delivery of chemotherapy
drugs and oxygen throughout tumors by increasing blood flow in mouse
models of breast and pancreatic cancer.
A clinical trial based on the
findings of this study is now underway according to their report in the
online journal Nature Communications.
"Angiotensin inhibitors are safe
blood pressure medications that have been used for over a decade in
patients and could be repurposed for cancer treatment," explains Rakesh
K. Jain, PhD, director of the
Steele Laboratory for Tumor Biology at MGH and senior author of the
"Unlike anti-angiogenesis drugs,
which improve tumor blood flow by repairing the abnormal structure of
tumor blood vessels, angiotensin inhibitors open up those vessels by
releasing physical forces that are applied to tumor blood vessels when
the gel-like matrix surrounding them expands with tumor growth."
Focusing on how the physical and
physiological properties of tumors can inhibit cancer therapies, Jain's
team previously found that losartan improves the distribution within
tumors of relatively large molecules called nanomedicines by inhibiting
the formation of collagen, a primary constituent of the extracellular
Why is losartan (Cozaar) prescribed?
Losartan is used alone or in combination with other medications
to treat high blood pressure. Losartan is also used to
decrease the risk of stroke in people who have high blood
pressure and a heart condition called left ventricular
hypertrophy (enlargement of the walls of the left side of the
heart). Losartan may not decrease the risk of stroke in African
Americans who have these conditions.
medication is also used to treat kidney disease in people
who have type 2 diabetes (condition in which the body
does not use insulin normally and therefore cannot control the
amount of sugar in the blood) and high blood pressure.
is in a class of medications called angiotensin II receptor
antagonists. It works by blocking the action of certain natural
substances that tighten the blood vessels, allowing the blood to
flow more smoothly and the heart to pump more efficiently.
The current study looked at whether
losartan and other drugs that block the action of angiotensin a
hormone with many functions in the body could release the elevated
forces within tumors that compress and collapse internal blood vessels.
These stresses are exerted when
cancer-associated fibroblasts (CAFs) specialized cells in the tumor
microenvironment proliferate and produce increased levels of both
collagen and a gel-like substance called hyaluronan.
The team's experiments in several mouse models
showed that both collagen and hyaluronan are involved in the compression
of blood vessels within tumors and that losartan inhibited production of
both molecules by CAFs through reducing the activation and overall
density of these cells.
Compared with drugs called ACE inhibitors,
which block angiotensin signaling in a different way, losartan and drugs
of its class termed angiotensin receptor blockers appeared better at
reducing compression within tumors. In models of breast and pancreatic
cancer, treatment with losartan alone had little effect on tumor growth,
but combining losartan with standard chemotherapy drugs delayed the
growth of tumors and extended survival.
"Increasing tumor blood flow in the absence of
anti-cancer drugs might actually accelerate tumor growth, but we believe
that combining increased blood flow with chemotherapy, radiation therapy
or immunotherapy will have beneficial results," explains Jain, the Cook
Professor of Radiation Oncology (Tumor Biology) at Harvard Medical
"Based on these findings in animal models, our
colleagues at the MGH Cancer Center have initiated a clinical trial to
test whether losartan can improve treatment outcomes in pancreatic
Co-lead authors of the Nature Communications
report are Vikash P. Chauhan, PhD, who completed this work as a doctoral
student at the Harvard School of Engineering and Applied Sciences,
working with Jain in the Steele Lab; and John D. Martin, a Massachusetts
Institute of Technology doctoral student currently part of Jain's team.
Additional co-authors are Hao Liu, Delphine Lacorre, Saloni Jain, Sergey
Kozin, Triantafyllos Stylianopoulos, Ahmed Mousa, Xiaoxing Han, Pichet
Adstamongkonkul, Peigen Huang and Yves Boucher, Steele Lab; and Zoran
Popović and Moungi Bawendi, Massachusetts Institute of Technology.
The study was supported primarily by National Cancer
Institute grants P01-CA080124, R01-CA126642, R01-CA085140, R01-CA115767
and R01-CA098706, and by Department of Defense Breast Cancer Research
Program Innovator Award W81XWH-10-1-0016. The MGH and Xtuit
Pharmaceuticals, a company co-founded by Jain, have applied for a patent
based on the work described in this paper.
Massachusetts General Hospital, founded in 1811, is the
original and largest teaching hospital of Harvard Medical School. The
MGH conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $775 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, reproductive biology, systems biology, transplantation biology
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