Synthesis and antiproliferative activity of podocarpane and totarane derivatives.

The synthesis of podocarpanes, including 12,19-dihydroxy-13-acetyl-8,11,13-podocarpatriene (23), isolated from Gaultheria yunnanensis and not previously synthesized, and totarane-type terpenoids, starting from the natural labdane trans-communic acid (15), is described. Their antiproliferative activities against MCF-7, T-84 and A-549 human tumoural cell lines are studied. An antiproliferative effect was induced by compounds 23, 27 and 28, with IC50 < 10 µM in two (27) or three cell lines (23 and 28). No correlation with log P values was observed. The totarane o-quinone 27, and especially the catechol 28, which is readily oxidisable to compound 27, were the most active compounds, highlighting the functional groups present in C11 and C12. Compound 28 showed limited toxicity in normal peripheral blood mononuclear cells (78.5% cell viability versus non-treated control cultures at 10 µM), and appeared to exert an antiproliferative effect in A-549 cells (IC50 0.6 µM) through a mechanism that involves the induction of apoptosis mediated by an increased Bax/Bcl-2 ratio. The results of the present study indicate that compound 28, at least, might be useful as an antitumoral agent. Further studies are required to elucidate the cellular and molecular elements involved in its effect, and the activity/toxicity in preclinical models.

Prospective evaluation of the conversion rate in the receptor status between primary breast cancer and metastasis: results from the GEICAM 2009-03 ConvertHER study.

The objective of this study was to determine the conversion rate of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) between primary tumors and metastatic lesions in advanced breast cancer. Patients with suspected diagnosis of locally recurrent or metastatic breast cancer, either at first relapse or after successive disease progressions, who had an appropriately preserved sample from a primary tumor and were scheduled for a biopsy of the recurrent lesion, were included. Blinded determinations of receptor status on paired samples were performed by immunohistochemistry and fluorescence in situ hybridization at a central laboratory and compared with those performed locally. Overall, 196 patients were included and 184 patients were considered evaluable. Reasons for non-evaluability included the inability to perform biopsy (n = 4) or biopsy results showing normal tissue (n = 3), benign disease (n = 3) or a second neoplasia (n = 2). Conversion rates determined at local level were higher than those determined centrally (HER2: 16 vs. 3 %, ER: 21 vs. 13 %, PR: 35 vs. 28 %, respectively). There was substantial agreement regarding the expression of HER2 in primary tumors and metastases, and ER at metastases, between local and central laboratories. PR at any site and ER at primary site showed moderate agreement. Oncologists altered their treatment plans in 31 % of patients whose tumor subtype had changed. These results reinforce the recommendation for performing confirmatory biopsies of metastases, not only to avoid misdiagnosis of breast cancer relapse, but also to optimize treatment (clinicaltrials.gov identifier: NCT01377363).