IJT - CIR - February 2024 - 57S

Cherian et al.
57S
Other Relevant Studies
Cytotoxicity
Adenosine. The cytotoxic effect of Adenosine in Swiss albino
mouse embryo fibroblasts (3T3 and 3T6) and immortalized
cervical cancer (HeLa) cells, cultured with and without
adenosine deaminase, was studied.39 [14C]Adenosine (.2-
2.5 μCi) was diluted with unlabeled Adenosine (to 105-
103 M) in .3 mL ofa solution containing serum-free medium,
50 mM phosphate buffer, and 10% serum. Both calfand horse
serum were used; however, horse serum did not contain
adenosine deaminase. Cells were exposed to Adenosine at
concentrations of0, .002, .005, .01, .02, .20, 1.0, and 2.0 mM,
and cultures were observed over a period of 1 week. When
Adenosine was added to cell cultures in a medium containing
horse serum, it was found to be toxic at low concentrations. In
10% calf serum, there was no effect on cell growth at low or
moderate Adenosine concentrations, while in medium containing
10% horse serum, there was definite inhibition of
growth at a concentration of .005 mM and a killing of cells at
.02 mM. Cell inhibition in calf serum was observed when
Adenosine was used at concentrations of 1.0 mM and higher.
When the same experiment was performed with horse serum
with the addition of 1 mM uridine to the cell culture medium,
toxic effects were not observed at any concentration up to
.2 mM.
Tumor Cell Proliferation
Adenosine. The effects of Adenosine on DNA synthesis and
cell growth in human (HT-29, T84, HRT-18, Colo320HSR)
and mouse (MCA-38) colorectal carcinoma cell lines were
studied.40 Cells were seeded in 24-well plates at 20,000 cells/
well. Adenosine was added at final concentrations of 1 μCi/
mL, 1 μM, with methyl-[3H]thymidine. Plates were incubated
for 36-48 h. DNA synthesis and cell proliferation were
stimulated in all cell lines tested, with a halfmaximal effective
concentration (EC50) of 2.8-30 μM, and a maximum stimulation
being reached at 10-100 μM. Effects were similar
among mouse and human cell lines.
Effect on Histamine Release
Adenosine Phosphate and Adenosine Triphosphate. Thirty-nine
patients with various dermatoses were used in a study evaluating
histamine release from human cutaneous mast cells following
intracutaneous injection with the polycondensation product ofNmethyl-p-methoxyphenethylamine
with formaldehyde (compound
48/80; causes histamine degranulation from mast cells),
Adenosine Triphosphate, adenosine diphosphate, or Adenosine
Phosphate.41 Solutions ofAdenosine Triphosphate (60 mg/mL),
adenosine diphosphate (30 mg/mL), Adenosine Phosphate
(37 mg/mL), and compound 48/80 (1 mg/mL) in distilled water
were prepared. The pH ofthese solutions was adjusted to 7.0 with
sodium hydroxide. Subjects were injected with .02 mL of each
solution. In addition, histamine dihydrochloride was also injected
(1,3,and 10 μg/mL), and used to compare the responses elicited
from the test substance. Injections of approximately 6 mg/mL
Adenosine Triphosphate caused a flare response similar to that of
histamine at < 10 μg/mL. Adenosine Triphosphate released
histamine at concentrations >1 mg/mL, while compound 48/80
stimulated histamine release in skin at concentrations >1 μg/mL.
Adenosine diphosphate had a weaker releasing effect, and
Adenosine Phosphate did not induce histamine release. In order
to determine that the skin reaction was due to released histamine,
the study was repeated in 17 subjects with the addition of the
antihistamine chlorcyclizine. After administration of the antihistamine
and Adenosine Triphosphate, the area of the flare
decreased significantly.
The effects of intradermal injections of Adenosine Phosphate
and Adenosine Triphosphate, as compared to intradermal
injections ofhistamine, were evaluated.42 The backs of
subjects were injected with 50 μL isosmotic phosphate
buffered saline containing Adenosine Triphosphate, Adenosine
Phosphate, histamine, compound 48/80, or phosphatebuffered
saline alone. Injections were carried out in 2.5-min
intervals. The area of erythema induced by the injection was
delineated at 30 seconds and after 4.5 min. Solutions that were
extremely acidic were neutralized with sodium hydroxide
prior to injection. Injection of Adenosine Triphosphate resulted
in immediate erythematous reaction of the surrounding
skin. This reaction faded after 1 min, and was replaced by
slightly darker erythema that lasted for up to 2 h. The extent of
these reactions was dose-dependent. No wheals were formed
after injection with Adenosine Phosphate or phosphatebuffered
saline. Adenosine Triphosphate produced wheals
in 5 out of 7 subjects injected with 180 nmol, and in all
subjects at higher doses, in a dose-dependent manner. Wheals
that resulted from 1080 nmol Adenosine Triphosphate were
approximately equal to wheals due to histamine (1.63 nmol).
Injections of Adenosine Triphosphate at high doses produced
sensations of persistent pain which was not observed with
injection of saline or histamine.
In order to evaluate the role of histamine and prostaglandins
in the inflammatory response to Adenosine Triphosphate,
the study was also performed with the addition of
pre-treatment with either diphenhydramine, cimetidine, indomethacin,
or doxantrazole. Erythema and wheal responses
were significantly suppressed with the addition of diphenhydramine
pre-treatment. Indomethacin, doxantrazole, and
cimetidine did not alter the Adenosine Triphosphate reaction.
Dermal Irritation and Sensitization
Irritation
In vitro
Adenosine. An in vitro skin irritation study was performed
using reconstructed human epidermis according to

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