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WILLIAM J. M. HRUSHESKY, M.D.
BOOKS:
Temporal Control of Drug Delivery. Hrushesky WJM,
Langer R, Theeuwes F (Editors). Annal NY Academy of Science,
Volume 618, 1991.
Circadian Cancer Therapy. Hrushesky WJM (Editor). CRC
Press, May 1994.
MONOGRAPHS:
Cancer Chronotherapy. Hrushesky WJM (Editor). Journal of
Infusional Chemotherapy 2 (2), April, 1992.
Scientific Basis for Circadian Cancer Therapy. Hrushesky WJM
(Editor). Journal of Infusional Chemotherapy 3 (3), July
1993.
Larry Scheving Symposium. Hrushesky WJM (Editor). Journal of
Infusional Chemotherapy 5 (1), Winter 1995.
PUBLICATIONS:
Wood PA, Bove K, You S, Chambers A, Hrushesky WJ. Cancer
growth and spread are saltatory and phase-locked to the
reproductive cycle through mediators of angiogenesis. Mol
Cancer Ther. 2005 Jul;4(7):1065-75
The frequency of breast cancer metastatic spread is affected
by the menstrual cycle phase of its resection. Breast cancer
growth, post-resection spread, and cure frequency are each
modulated by the estrous cycle in C(3)HeB/FeJ mice. Tumor
metastases are 2- to 3-fold more frequent when the resection
is done during diestrus as compared with estrus. Tumor
angiogenesis is essential for both cancer growth and lethal
metastatic cancer spread. The balance between vascular
endothelial growth factor (VEGF) and basic fibroblast growth
factor (bFGF) modulates new blood vessel formation and blood
vessel permeability. Sex hormones modulate the expression of
these key angiogenesis regulators in the endometrium and
uterus. We, therefore, asked whether the estrous cycle
modulates the density of CD31-positive vessels within the
tumor, the permeability of tumor blood vessels, levels of
VEGF and bFGF immunoreactive protein in normal breast and
breast cancer, and whether expression of these genes are
modulated by the estrous cycle stage in C(3)HeB/FeJ mice. We
find that tumor blood vessel density and blood volume do not
vary throughout the cycle; however, tumor capillary
permeability is regulated by the estrous cycle being highest
in diestrus, the cycle stage associated with the highest
cancer growth rate and the highest frequency of
post-resection cancer metastasis. VEGF protein levels in
breast cancer are >100-fold higher than in normal breast.
VEGF protein in this mammary tumor varies with the estrus
cycle with highest levels in proestrus. In a non-breast
tumor, methylcholantrenene A sarcoma, from CD(2)F(1) mice,
tumor VEGF protein also varies with the estrus cycle with
highest levels in proestrus and diestrus. VEGF gene
expression in the mammary tumor does not change
significantly across the cycle, but is modulated by the
cycle in normal breast tissue. bFGF protein concentration is
6-fold higher in normal breast than in breast cancer. bFGF
protein pattern in both tumor and breast are similar,
opposite to VEGF, and affected by oophorectomy. bFGF message
is modulated by the cycle in both breast cancer and normal
breast. The changes in breast cancer capillary permeability,
VEGF, and bFGF that occur during each fertility cycle, in
breast tissue and breast cancer, putatively in response to
cyclical changes in sex hormones, might contribute, at least
in part, to both the modulation of cancer growth and
post-resection breast cancer spread by the fertility cycle.
These fertility cycle-induced effects on tumor biology also
seem to extend to non-breast cancer biology.
Wood PA, Hrushesky WJ. Sex cycle
modulates cancer growth. Breast Cancer Res Treat. 2005
May;91(1):95-102
HYPOTHESIS: Among premenopausal women, both post-resection
metastatic potential and tumor growth rate are influenced by
the menstrual cycle. There is strong support for the former
in large retrospective studies of surgical resection timing
within the menstrual cycle and the following experiments
were conducted to critically evaluate the latter. METHODS:
We studied a transplantable breast cancer of C3HeB/FeJ mice
(3 studies), and a transplantable methylcholantherene A
induced sarcoma of CD2F1 mice (2 studies). We concurrently
measured local cancer size and estrous cycle stage up to
twice and at least once each day. There is a natural
individual variability in the average length of normal
estrus (3-1/2 to 7 days) cycle in mice. We assessed the
effect of the cycle stage and cycle duration on tumor size.
RESULTS: We found identical estrous cycle stage coordination
of cancer size, and identical effects of cycling frequency
across all studies in each of these two tumors, both of
which express both estrogen receptor alpha and progesterone
receptor. Little or no change in cancer size occurs during
proestrus (preovulatory phase) and estrus (periovulatory
phase); tumor size increases several fold during diestrus
(post-ovulatory phase); and the tumor shrinks partially as
the next proestrus phase is approached. Across both mouse
strains and tumor types, mice whose average cycle length is
briefer (faster cyclers), have slower average tumor growth
rate than those with longer cycles (slower cyclers) who have
faster tumor growth rates. CONCLUSION: The virtually
identical modulation of tumor size and cancer growth rate,
in each of two very different transplantable cancers (one,
classically sex-hormone-dependent, and the other, never
previously recognized as hormone dependent) growing in two
unrelated inbred mouse strains, indicates that the fertility
cycle related host factors affect cancer size and growth
rate. These experimental findings suggest that cancer cell
proliferation of both breast and non-breast cancers in
premenopausal women may be meaningfully coordinated by the
menstrual cycle. If this proves to be the case, then any
therapeutic strategy targeting proliferating cancer cells
should be most effective against cancer of cycling women
when given during the follicular phase of their menstrual
cycles.
You S, Wood PA, Xiong Y, Kobayashi M,
Du-Quiton J, Hrushesky WJ. Daily coordination of cancer
growth and circadian clock gene expression. Breast Cancer
Res Treat. 2005 May;91(1):47-60
BACKGROUND: Circadian coordination in mammals is
accomplished, in part, by coordinate, rhythmic expression of
a series of circadian clock genes in the central clock
within the suprachiasmatic nuclei (SCN) of the hypothalamus.
These same genes are also rhythmically expressed each day
within each peripheral tissue. METHODS: We measured tumor
size, tumor cell cyclin E protein, tumor cell mitotic index,
and circadian clock gene expression in liver and tumor cells
at six equispaced times of day in individual mice of a 12-h
light, 12-h dark schedule. RESULTS: We demonstrate that
C3HFeJ/HeB mice with transplanted syngeneic mammary tumor
maintain largely normal circadian sleep/activity patterns,
and that the rate of tumor growth is highly rhythmic during
each day. Two daily 2.5-fold peaks in cancer cell cyclin E
protein, a marker of DNA synthesis, are followed by two
daily up-to-3-fold peaks in cancer cell mitosis (one minor,
and one major peak). These peaks are, in turn, followed by
two prominent daily peaks in tumor growth rate occurring
during mid-sleep and the second, during mid-activity. These
data indicate that all therapeutic targets relevant to tumor
growth and tumor cell proliferation are ordered in tumor
cells within each day. The daily expression patterns of the
circadian clock genes Bmal1, mPer1, and mPer2, remain
normally circadian coordinated in the livers of these tumor
bearing mice. Bmal1 gene expression remains circadian
rhythmic in cancer cells, although damped in amplitude, with
a similar circadian pattern to that in normal hepatocytes.
However, tumor cell mPer1 and mPer2 gene expression patterns
fail to maintain statistically significant daily rhythms.
CONCLUSION: We conclude that, if core circadian clock gene
expression is essential to gate tumor cell proliferation
within each day, then there may be substantial redundancy in
this timing system. Alternatively, the daily ordering of
tumor cell clock gene expression may not be essential to the
daily gating of cancer cell DNA synthesis, mitosis and
growth. This would indicate that host central SCN-mediated
neuro-humoro-behavioral controls and/or daily light-induced
changes in melatonin or peripherally-induced rhythms such as
those resulting from feeding, may be adequate for the daily
coordination of cancer cell expression of proliferation
related therapeutic targets.
You S, Li W, Kobayashi M, Xiong Y,
Hrushesky W, Wood P. Creation of a stable mammary tumor cell
line that maintains fertility-cycle tumor biology of the
parent tumor. In Vitro Cell Dev Biol Anim. 2004
Jul-Aug;40(7):187-95
A mammary tumor cell line, designated MTCL, was successfully
established from a mouse primary mammary tumor (MTP). The
MTCL cells retain cytokeratin and both estrogen receptor
(ER) and progesterone receptor (PR) in vitro. In vitro
exposure of MTCL cells to progesterone causes a decrease in
the cellular (3)H-thymidine uptake, indicating an inhibition
by progesterone on MTCL cellular deoxyribonucleic acid
synthesis, whereas exposure of the cells to a high dose of
estrogen (15 pg/ml) for 48 h causes an increase of
(3)H-thymidine uptake. We inoculated both MTP or MTCL tumor
cells into normal cycling female C(3)HeB/FeJ mice and
demonstrated that the post-resection metastatic recurrence
of MTCL tumors, like the original MTP tumors, depends on the
time of tumor resection within the mouse estrous-cycle
stage. Both MTCL and MTP tumors have similar histological
appearances with the exception of less extensive tumor
necrosis and higher vascularity in MTCL tumors. Equivalent
levels of sex hormone receptors (ER alpha, ER beta, and PR),
epithelial growth hormone receptors (Her2/neu, EGFR1), tumor
suppressors (BRCA1, P53), and cell apoptosis-relevant
protein (bcl-xl) were found in these in vivo tumors by
immunohistochemistry. Cyclin E protein, however, was
significantly higher in MTP tumors compared with MTCL
tumors. Our results indicate that MTCL cells retain many of
the biologic features of the original MTP primary tumor
cells, and to our knowledge, it is the first in vitro cell
line that has been shown to maintain the estrous-cycle
dependence of in vivo cancer metastasis.
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