Neoadjuvant chemotherapy for epithelial ovarian cancer--role of apoptosis.
BACKGROUND
Ovarian cancer is one of the most frequently fatal gynecological cancers because most cases are diagnosed at an advanced stage. Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumor progression. Little is known about the effect of various treatment regimens on the distribution of molecular markers of apoptosis in epithelial ovarian cancer. The objective of this study was to compare the expression levels of both proapoptotic and antiapoptotic proteins p53, p73, Bcl-2, Bcl-XL and survivin in the ascitic cells and tumor samples of patients undergoing treatment with two different regimens.


METHODS
A total of 24 patients with untreated epithelial ovarian cancer were randomized into two groups of 12 each. Group 1 patients received three cycles of chemotherapy prior to surgery and three cycles after surgery and group 2 patients received six cycles of chemotherapy prior to surgery. The expression of apoptosis-related proteins was analyzed in ascitic fluid and tumor samples by Western blotting and immunohistochemistry. The apoptotic index was also determined in these samples by the TUNEL assay.


RESULTS
Significant decreases in antiapoptotic bcl-2 and survivin were seen, accompanied by increases in apoptotic index in tumors that had undergone chemotherapy as compared to the baseline ascites samples. No significant change in bcl-XL was observed. A significant decrease in proapoptotic p53 was also seen. No expression of p73 was observed in tumors or ascites. The findings were similar in groups 1 and 2 patients and were not statistically significantly different, perhaps due to the small sample size (n=12) of each group.


CONCLUSIONS
The above findings indicate that chemotherapy in ovarian carcinoma leads to an increase in apoptosis by a p53-independent pathway, which involves the downregulation of antiapoptotic Bcl-2 and survivin but not Bcl-XL. Furthermore, administering neoadjuvant chemotherapy (six cycles) as an alternative form of therapy for advanced epithelial ovarian cancer is more effective in inducing apoptosis than three cycles. However, the findings of this study need to be corroborated using a larger sample.
Dutta
Tania
T
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
Sharma
Himani
H
Kumar
Lalit
L
Dinda
A K
AK
Kumar
Sunesh
S
Bhatla
Neerja
N
Singh
Neeta
N
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D017024:Chemotherapy, Adjuvant; D015853:Cysteine Proteinase Inhibitors / Q000302:isolation & purification; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000302:isolation & purification; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000302:isolation & purification; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D015853:Cysteine Proteinase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin