LE Magazine April 2003
Silicon
Effects of germanium and silicon on
bone mineralization.
The chemical properties of germanium (Ge) are similar to
silicon (Si). This study investigated whether Ge can
substitute for, or is antagonistic to, Si in bone formation.
Sixty male weanling Sprague-Dawley rats were randomly assigned
to treatment groups of 12 and 6 in a 2 x 4 factorially
arranged experiment. The independent variables were, per gram
fresh diet, Si (as sodium metasilicate) at 0 or 25 micrograms
and Ge (as sodium germanate) at 0, 5, 30 or 60 micrograms.
Results confirmed that Ge does not enhance Si deprivation and
provided evidence that Ge apparently can replace Si in
functions that influence bone composition. When Si was lacking
in the diet, calcium and magnesium concentrations of the femur
were decreased; this was reversed by feeding either Ge and/or
Si. Similar effects were found for zinc, sodium, iron,
manganese and potassium of vertebra. There were some responses
to Si deprivation that Ge could not reverse; Ge did not
increase femur copper, sodium or phosphorus or decrease
molybdenum of vertebra, effects that were evoked by Si
supplementation. Additionally, some findings suggested that 60
micrograms Ge/g diet could be a toxic intake for the rat. On
the other hand, some responses induced by Ge indicate that
this element may be acting physiologically other than as a
substitute for Si. Germanium itself affected bone composition.
Germanium supplementation decreased Si and molybdenum in the
femur and increased DNA in tibia. Regardless of the amount of
Si fed, animals fed 30 micrograms Ge/g diet had increased
tibial DNA compared to animals fed 0 or 60 micrograms Ge;
however, tibial DNA of animals fed 30 micrograms Ge was not
statistically different from those animals fed 5 micrograms
Ge. Thus, Ge may be of nutritional importance.
Biol Trace Elem Res 1994
Aug;42(2):151-64
Silicon deprivation decreases collagen
formation in wounds and bone, and ornithine transaminase
enzyme activity in liver.
We have shown that silicon (Si) deprivation decreases the
collagen concentration in bone of nine-week-old rats. Finding
that Si deprivation also affects collagen at different stages
in bone development, collagen-forming enzymes or collagen
deposition in other tissues would have implications that Si is
important for both wound healing and bone formation.
Therefore, 42 rats in experiment one and 24 rats in experiment
two were fed a basal diet containing 2 or 2.6 microg Si/g,
respectively, based on ground corn and casein, and
supplemented with either 0 or 10 microg Si/g as sodium
metasilicate. At three weeks, the femur was removed from 18 of
the 42 rats in experiment one for hydroxyproline analysis. A
polyvinyl sponge was implanted beneath the skin of the upper
back of each of the 24 remaining rats. Sixteen hours before
termination and two weeks after the sponge had been implanted,
each rat was given an oral dose of 14C-proline (1.8
microCi/100 g body wt). The total amount of hydroxyproline was
significantly lower in the tibia and sponges taken from
Si-deficient animals than Si-supplemented rats. The
disintegrations per minute of 14C-proline were significantly
higher in sponge extracts from Si- deficient rats than
Si-supplemented rats. Additional evidence of aberrations in
proline metabolism with Si deprivation was that liver
ornithine aminotransferase was significantly decreased in
Si-deprived animals in experiment two. Findings of an
increased accumulation of 14C-proline and decreased total
hydroxyproline in implanted sponges and decreased activity of
a key enzyme in proline synthesis (liver ornithine
aminotransferase) in Si-deprived animals indicates an
aberration in the formation of collagen from proline in sites
other than bone that is corrected by Si. This suggests that Si
is a nutrient of concern in wound healing as well as bone
formation.
Biol Trace Elem Res 2002
Dec;89(3):251-61
Stem cells
Eradication of multiple myeloma and
breast cancer cells by TH9402-mediated photodynamic therapy:
implication for clinical ex vivo purging of autologous stem
cell transplants.
High-dose chemotherapy combined with autologous
transplantation using bone marrow or peripheral blood-derived
stem cells (PBSC) is now widely used in the treatment of
hematologic malignancies as well as some solid tumors like
breast cancer (BC). However, some controversial results were
recently obtained in the latter case. The presence of
malignant cells in the autograft has been associated with the
recurrence of the disease, and purging procedures are needed
to eliminate this risk. The aim of this study was to evaluate
the potential of the photosensitizer 4,5-dibromorhodamine
methyl ester (TH9402), a dibrominated rhodamine derivative, to
eradicate multiple myeloma (MM) and BC cell lines, while
sparing more than 50% of normal pluripotential blood stem
cells from healthy volunteers. The human BC MCF-7 and T-47D
and MM RPMI 8226 and NCI-H929 cell lines were used to optimize
the photodynamic purging process. Cell concentration and the
cell suspension thickness as well as the dye and light doses
were varied in order to eventually treat 1-2 L of apheresis.
The light source consisted of two fluorescent scanning tubes
emitting green light centered about 515 nm. The cellular
uptake of TH9402 was measured during the incubation and
washout periods and after photodynamic treatment (PDT) using
spectrofluorometric analysis. The limiting dilution assay
showed that an eradication rate of more than five logs is
obtained when using a 40 minute incubation with 5 to 10 microM
dye followed by a 90 minute washout period and a light dose of
5 to 10 J/cm2 (2.8 mW/cm2) in all cell lines. Agitating the 2
cm thick cell suspension containing 20 x 10(6) cells/mL during
PDT was essential for maximal photoinactivation. Experiments
on mobilized PBSC obtained from healthy volunteers showed that
even more drastic purging conditions than those found optimal
for maximal eradication of the malignant cell lines were
compatible with a good recovery of hematopoietic progenitors
cells. The absence of significant toxicity towards normal
hematopoietic stem cells, combined with the five logs
eradication of cancer cell lines induced by this procedure
suggests that TH9402 offers an excellent potential as an ex
vivo photodynamic purging agent for autologous transplantation
in MM and BC treatment.
Photochem Photobiol 2000
Dec;72(6):780-7
Prevention of graft-versus-host
disease while preserving graft-versus-leukemia effect after
selective depletion of host-reactive T cells by photodynamic
cell purging process.
In this study, we investigated the possibility of selective
depletion of donor alloantigen-specific T-cells from C57BL/6
(H-2(b)) mice to prevent graft-versus-host disease (GVHD).
These cells were first activated with irradiated BALB/c
(H-2(d)) host spleen cells in a five-day mixed lymphocyte
culture. Following this activation, a photoactive rhodamine
derivative called 4,5-dibromorhodamine 123 (TH9402), was
added. This compound is selectively retained in the
mitochondria of activated host-reactive cells but not tumor-
or third-party-specific resting cells. The treated cells were
subsequently exposed to visible light (514 nm) to deplete the
TH9402-enriched activated host-reactive cells. Treatment with
photodynamic cell purging process (PDP) inhibited antihost
responses measured by cytotoxic T-lymphocytes (CTL) by 93%,
and interferon-gamma production by 66%. By contrast, anti-BCL1
(BALB/c-origin leukemia/lymphoma) and anti-third-party C3H/HeJ
(H-2(k)) responses were preserved. PDP-treated primed C57BL/6
cells were further tested in vivo. All lethally irradiated
BALB/c mice inoculated with BCL1 cells and T-cell-depleted
bone marrow cells developed leukemia by day +30, with 50%
mortality by 100 days. All mice died of GVHD after addition of
5 x 10(6) untreated primed C57BL/6 cells. However, addition of
same numbers of PDP-treated cells allowed 90% of the
recipients to survive more than 100 days without detectable
BCL1 tumor cells and free of GVHD. Moreover, PDP-treated
primed C57BL/6 cells retained the ability to induce GVHD in
the third-party C3H/HeJ mice. These data suggest that PDP can
selectively deplete host alloantigen-specific T-cells for GVHD
prevention and immune and antileukemia function preserve.
Blood 2002 May 1;99(9):3083-8
Continued on Page 2 of 2
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