The analgesic drug dipyrone is used to treat side effects (including pain and fever) of cancer chemotherapeutic agents. Dipyrone is metabolized to 4-aminoantipyrine (4-AA), a PGE2-dependent blocker and inhibitor of cyclooxygenase (COX). We evaluated the genotoxic, mutagenic, apoptotic, and immunomodulatory activities of 4-AA in vivo and the effects of its combination with the antineoplastic drugs doxorubicin, cisplatin, and cyclophosphamide. 4-AA did not cause genotoxic/mutagenic damage, splenic phagocytosis, or leukocyte alterations. However, when combined with the antineoplastic agents, 4-AA decreased their genotoxic, mutagenic, apoptotic, and phagocytic effects. These results suggest that 4-AA might interfere with DNA damage-mediated chemotherapy.
The increased incidence of cancer and its high treatment costs have encouraged
the search for new compounds to be used in adjuvant therapies for this disease.
This study discloses the synthesis of
(Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl)
amino)-4-oxobut-2-enoic acid (IR-01) and evaluates not only the action of this
compound on genetic integrity, increase in splenic phagocytosis and induction of
cell death but also its effects in combination with the commercial
chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was
designed and synthesized based on two multifunctionalyzed structural fragments:
4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant
and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl,
a cytotoxic agent. The results indicated that IR-01 is an effective
chemoprotector because it can prevent clastogenic and/or aneugenic damage, has
good potential to prevent genomic damage, can increase splenic phagocytosis and
lymphocyte frequency and induces cell death. However, its use as an adjuvant in
combination with chemotherapy is discouraged since IR-01 interferes in the
effectiveness of the tested chemotherapeutic agents. This is a pioneer study as
it demonstrates the chemopreventive effects of IR-01, which may be associated
with the higher antioxidant activity of the precursor structure of
4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.
Despite rapid advances in both the early detection and treatment of cancer, the
mortality from this disease remains high, which justifies the development of new
products that are more selective and effective and have fewer side effects.
Accordingly, a novel ester was synthesized that contains two pharmacophores with
important biological activities: (I) 4-aminoantipyrine, which has
anti-inflammatory and antioxidant effects, and (II) the pharmacophore
1,4-dioxo-butenyl, which has cytotoxic activity. When administered alone, this
compound is non-genotoxic, and it does not cause an increasing in splenic
phagocytosis. Nevertheless, it can induce cell death. When administered in
combination with commercial chemotherapeutic agents, such as doxorubicin,
cisplatin, and cyclophosphamide, the ester shows antigenotoxic activity and
decreases phagocytosis and reduces the potential to cause cell death. These
results indicate that the compound should not be used in combination with
chemotherapeutic agents that exert their effect through DNA damage, an important
feature of antitumor drugs.
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