PHARMACOLOGICAL & TOXICOLOGICAL EFFECTS OF PACLITAXEL
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Date
2014
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CSKHPKV, Palampur
Abstract
The present investigation was conducted to study in vitro cytotoxicity, apoptosis and changes in
cell cycle kinetics induced by paclitaxel on C6 (Rattus norvegicus glioma) and CHO-K1 (Chinese
hamster ovarian carcinoma) cell lines. In this study, percentage cytotoxicity against cell lines was
evaluated by Sulphorhodamine (SRB) assay. The percentage of surviving cells fell after 48 hours
of treatment and IC50 values were observed between 0.5 to 0.75 and 0.25 to 0.75 μg/ml in C6 and
CHO-K1 cells, respectively. Cells incubated in high concentrations of paclitaxel had increased
survivability compared with cells treated with lower concentrations of the drug. No significant
cytotoxicity was observed after 24 hours of treatment. Paclitaxel induced apoptosis by caspase 3/7
activation and caused accumulation of cells in G2/M phase of cell cycle in both the cell lines. Upon
fluorescent microscopy, both the cell lines lost their morphology, confluency and adherence after
24 hours but the effects were much more pronounced after 48 hours of treatment. In vivo
toxicological studies were also conducted in adult wistar rats to evaluate the highest non toxic dose
level of intra peritoneal administration of Paclitaxel-Cremophor EL formulation at 0.30 (G1), 1.20
(G2), 2.32 (G3) and 3.20 (G4) mg/kg at 7 day interval over a period of 21 days (3 times in total). In
acute toxicity studies alopecia and tachypnea was observed in G4. No other signs of acute toxicity
and no mortality was observed in any of the dose groups. After repeated dosing, at 21st day, serum
aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatinine phosphokinase
levels were significantly increased in G3 and G4 and total serum protein, albumin and alkaline
phosphatase levels were also increased in G4. No significant changes were observed in serum
globulin levels in any of the dose groups. Red Blood cell and lymphocytic count was significantly
decreased in groups G3 and G4 and white blood cell, neutrophil count, hematocrit percentage and
haemoglobin concentration was also decreased in G4. Histopathological changes were observed
mainly as nuclear fragmentation, apoptosis and cellular damage in liver, heart, spleen, kidney,
mesenteric lymph nodes, lungs and testes in G3 and G4 but the severity of lesions was much higher
in G4. The in vitro data suggested that paclitaxel will be most effective clinically when there is
prolonged exposure of tumour to the drug rather than increasing concentration of drug in the
biophase. Based on in vivo results, the highest non-toxic dose of formulation was estimated to be
1.20 mg/kg in rats, under this study condition and equivalent human dose was estimated to be
0.1332 mg/kg.
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