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Abstract: Objective. : To analyze the expression of phospholipase A2 (PLA2) isoforms and its relationship with matrix metalloproteinase (MMP) expression and clinical parameters in advanced-stage (FIGO III–IV) ovarian carcinoma. Methods. : Seventy-seven fresh frozen effusions from ovarian carcinoma patients were studied for messenger RNA (mRNA) expression of 10 secretory PLA2 (sPLA2) isoforms (IB, IIA/D/E/F, III, V, X, XII and XIII), the PLA2 receptor (sPLA2R), cytoplasmic PLA2 (cPLA2), PLA2-activating protein (PLAP) and MMP-2 using reverse transcription polymerase chain reaction (RT-PCR). Phosphorylated cPLA2 (p-cPLA2) protein expression was studied in 52 effusions using immunohistochemistry. MMP-2 and MMP-9 activity was evaluated in 22 and 20 effusions, respectively, using zymography. Expression was analyzed for correlation with clinicopathologic parameters, chemotherapy status and survival. Results. : PLA2 isoforms, sPLA2R, PLAP and MMP-2 mRNA was expressed in >95% of specimens. p-cPLA2 protein was expressed in 46/52 (88%) effusions. MMP-2 activity was found in all specimens, while that of MMP-9 was detected in 19/20 effusions. MMP-2 was found to be co-expressed with p-cPLA2 (p =0.003) and sPLA2-IIA (p =0.021). Lower expression of sPLA2-IIA (p <0.001) and higher expression of sPLA2-V (p =0.038) and sPLA2-XIII (p =0.001) was found in post-chemotherapy effusions. In univariate survival analysis, higher levels of sPLA2-V correlated with better overall (OS, p =0.021) and progression-free (PFS, p =0.025) survival. For patients with post-chemotherapy effusions, FIGO stage IV and higher PLAP mRNA expression correlated with worse OS (p =0.005 for both PLAP and stage), while higher PLAP (p =0.025) and sPLA2-XII (p =0.027) levels and FIGO stage IV (p <0.001) correlated with shorter PFS. In Cox multivariate analysis, PLAP expression (p =0.022) and FIGO stage (p =0.036) independently predicted poor OS, while higher sPLA2-XII levels (p =0.04) and FIGO stage (p =0.003) were independent predictors of shorter PFS. Conclusions. : The present study documents for the first time expression of PLA2 isoforms, sPLA2R and PLAP in ovarian carcinoma. PLA2 isoenzyme expression differs in pre- and post-chemotherapy specimens. PLAP and sPLA2-XII may be independent predictors of poor outcome for patients with post-chemotherapy effusions. [Copyright &y& Elsevier]

This study was conducted to evaluate the frequency and prognostic impact of TP53 alterations stratified for the TP53 codon 72 polymorphism (c.215G>C, p.Arg72Pro) in a cohort of 109 patients with advanced ovarian carcinomas. TP53 sequence variants were observed in 80 of the 109 (73.4%) tumors and were significantly associated with grade of differentiation (P=0.001). A tendency towards higher frequency of sequence variants in tumors with higher FIGO stages was seen (P=0.05). The type of TP53 sequence variant (transition A:T>G:C vs. G:C>A:T at CpG dinucleotides, and transversion G:C>T:A) had significant correlation with patients' age (P=0.04) with more A:T>G:C in patients over 60 years old. No significant associations were found between frequency of sequence variants and age at diagnosis, histological type, size of residual tumor after primary surgery, or long-term survival. Analyses of the codon 72 polymorphism in tumor DNA gave a higher frequency of homozygosity/hemizygosity than expected from the population frequency, particularly for the Pro allele. Tumors homozygous or hemizygous for the Pro allele had significantly higher frequency of TP53 sequence variants, particularly of the nonmissense type (P=0.002), and patients with these types of alterations had significantly shorter survival (P=0.04). TP53 protein accumulation, determined by immunohistochemistry (IHC), was found in 67.9% (74 out of 109) of the tumors, was significantly more common among serous than nonserous ovarian carcinomas (P=0.008), and had a significant effect on progression-free survival (P=0.03). p63 (TP73L; formerly TP63) and p73 (TP73) protein accumulation detected by IHC was seen in 67.9 and 0% of the tumors, respectively. A significantly higher frequency of p63-positive cases was seen among serous tumors (P=0.008) and tended to increase with increasing FIGO stages (P=0.05), but had no significant effect on survival. No association between p63 protein accumulation and TP53 protein accumulation was seen. Hum Mutat 24:21-34, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

MGI Pharma is developing irofulven, a semi-synthetic compound derived from illudin S, a toxin from the Omphalotus illudens mushroom, for the potential treatment of refractory and relapsed tumors, including ovarian, prostate, hepatocellular, breast, lung and colon cancers. Phase II trials of the compound as a monotherapy or in combination therapies are ongoing for a number of these indications.