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Docetaxel with estramustine for prostate cancer
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Researchers pHLIP tumour targets A new technique, using the protein fragment pH (Low) Insertion Peptide (pHLIP), has been used in vivo to target tumours in mice by researchers at Yale University (Proc Natl Acad Sci USA published online May 1, 2007; DOI:10.1073/pnas.0702439104). In a previous study the team showed that pHLIP could deliver cell-
pHLIP allows tumour-targeting via pH
impermeable molecules across the plasma membrane of cells at a low pH, initiating possibilities of pHLIP acting as a syringe by inserting itself into the cell membrane and injecting compounds into the cell. At a neutral pH (normal physiological conditions), the equilibrium is towards water, which explains pHLIP’s low affinity for cells in healthy tissue. In this study, Engelman and colleagues (Yale University, New Haven, CT, USA) injected fluorescence-labelled pHLIP into mouse models of breast adenocarcinoma and rat models of inflammatory arthritis. The researchers found that labelled pHLIP found its way to solid acidic tumours in the mice and acidic tissue in the rats. “The most important finding in this study is that acidic tissue can be targeted by the pHLIP peptide and since early tumours are acidic, this gives an opening for diagnosis and
therapy”, Donald Engelman told The Lancet Onoclogy. Stefano Fais (Instituto Superiore di Sanita, Rome, Italy) says: “this article provides the evidence that an acidic pH may represent a valuable method to insert peptides in target cells”. Fais thinks that these results will be essential for selective treatment for tumours. “We have many biotechnological molecules that may work in tumours, but whose action is markedly impaired by the very adverse environmental conditions, including acidity. This may represent a way to increase the efficacy of these drugs through acidic pH.” Engelman is hoping to work next on “targeting breast cancer by attaching agents to pHLIP, targeting them to tumours, and activating them to destroy the tumour tissue selectively”.
Nayanah Siva
Docetaxel with estramustine for prostate cancer The results of a new randomised phase II study headed by Jean-Christophe Eymard (Institut Jean-Godinot, Reims, France) indicate that docetaxel in combination with estramustine is an active and well-tolerated option for the treatment of metastatic hormone-refractory prostate cancer (HRPC) (Ann Oncol, published online April 13, 2007; DOI:10.1093/annonc/ mdm083). Estramustine consists of an oestrogen moiety linked to a nitrogen mustard. Initial expectations that it would target breast-cancer and prostatecancer cells for killing by DNA alkylation turned out to be incorrect, explains William Berry (Cancer Centers of North Carolina, Raleigh, NC, USA). Instead, he notes, “estramustine affects microtubules, which has led to its clinical development in combination with other microtubule-binding agents, including taxanes”. However, 470
Eymard comments: “although some in-vitro work and previous phase I and II studies of the docetaxel– estramustine (DE) combination seemed to indicate a synergistic antitumour effect, its benefit in clinical practice remained controversial“. For their study, the researchers enrolled 92 patients with metastatic HRPC from 12 centres across France. In each 3-week treatment cycle, the 47 patients in the DE group received 70mg/m2 docetaxel on day 2 and 280 mg estramustine twice daily on days 1–5; the 44 patients in the docetaxel only (D) group received 75mg/m2 docetaxel on day 1. One patient randomised to the DE group received no treatment. Patients were given prophylatic warfarin to prevent estramustine-related thromboembolism. A sustained reduction of at least 50% from baseline in serum prostate-specific antigen occurred
in 68% (95% CI 55–81) and 30% (16–43) of patients in the DE and D groups, respectively. Median time to progression was 5·7 months (4·7–6·8) and 2·9 months (2·0–6·9), and median survival was 19·3 months (14·6–25·9) and 17·8 months (11·8–20·9) in the DE and D groups, respectively. Toxic effects were similar in both groups. ’Estramustine treatment certainly benefits patients with HRPC“, says Eymard. Other randomised trials and a meta-analysis (in which he and Berry are involved) also suggest that the DE combination is “an interesting and reasonable option for patients with no thromboembolic history“, notes Eymard. Berry agrees that the current evidence supports the use of the combination, but adds that when he uses estramustine, he fully anticoagulates with warfarin.
Jane Bradbury http://oncology.thelancet.com Vol 8 June 2007
Researchers pHLIP tumour targets A new technique, using the protein fragment pH (Low) Insertion Peptide (pHLIP), has been used in vivo to target tumours in mice by researchers at Yale University (Proc Natl Acad Sci USA published online May 1, 2007; DOI:10.1073/pnas.0702439104). In a previous study the team showed that pHLIP could deliver cell-
pHLIP allows tumour-targeting via pH
impermeable molecules across the plasma membrane of cells at a low pH, initiating possibilities of pHLIP acting as a syringe by inserting itself into the cell membrane and injecting compounds into the cell. At a neutral pH (normal physiological conditions), the equilibrium is towards water, which explains pHLIP’s low affinity for cells in healthy tissue. In this study, Engelman and colleagues (Yale University, New Haven, CT, USA) injected fluorescence-labelled pHLIP into mouse models of breast adenocarcinoma and rat models of inflammatory arthritis. The researchers found that labelled pHLIP found its way to solid acidic tumours in the mice and acidic tissue in the rats. “The most important finding in this study is that acidic tissue can be targeted by the pHLIP peptide and since early tumours are acidic, this gives an opening for diagnosis and
therapy”, Donald Engelman told The Lancet Onoclogy. Stefano Fais (Instituto Superiore di Sanita, Rome, Italy) says: “this article provides the evidence that an acidic pH may represent a valuable method to insert peptides in target cells”. Fais thinks that these results will be essential for selective treatment for tumours. “We have many biotechnological molecules that may work in tumours, but whose action is markedly impaired by the very adverse environmental conditions, including acidity. This may represent a way to increase the efficacy of these drugs through acidic pH.” Engelman is hoping to work next on “targeting breast cancer by attaching agents to pHLIP, targeting them to tumours, and activating them to destroy the tumour tissue selectively”.
Nayanah Siva
Docetaxel with estramustine for prostate cancer The results of a new randomised phase II study headed by Jean-Christophe Eymard (Institut Jean-Godinot, Reims, France) indicate that docetaxel in combination with estramustine is an active and well-tolerated option for the treatment of metastatic hormone-refractory prostate cancer (HRPC) (Ann Oncol, published online April 13, 2007; DOI:10.1093/annonc/ mdm083). Estramustine consists of an oestrogen moiety linked to a nitrogen mustard. Initial expectations that it would target breast-cancer and prostatecancer cells for killing by DNA alkylation turned out to be incorrect, explains William Berry (Cancer Centers of North Carolina, Raleigh, NC, USA). Instead, he notes, “estramustine affects microtubules, which has led to its clinical development in combination with other microtubule-binding agents, including taxanes”. However, 470
Eymard comments: “although some in-vitro work and previous phase I and II studies of the docetaxel– estramustine (DE) combination seemed to indicate a synergistic antitumour effect, its benefit in clinical practice remained controversial“. For their study, the researchers enrolled 92 patients with metastatic HRPC from 12 centres across France. In each 3-week treatment cycle, the 47 patients in the DE group received 70mg/m2 docetaxel on day 2 and 280 mg estramustine twice daily on days 1–5; the 44 patients in the docetaxel only (D) group received 75mg/m2 docetaxel on day 1. One patient randomised to the DE group received no treatment. Patients were given prophylatic warfarin to prevent estramustine-related thromboembolism. A sustained reduction of at least 50% from baseline in serum prostate-specific antigen occurred
in 68% (95% CI 55–81) and 30% (16–43) of patients in the DE and D groups, respectively. Median time to progression was 5·7 months (4·7–6·8) and 2·9 months (2·0–6·9), and median survival was 19·3 months (14·6–25·9) and 17·8 months (11·8–20·9) in the DE and D groups, respectively. Toxic effects were similar in both groups. ’Estramustine treatment certainly benefits patients with HRPC“, says Eymard. Other randomised trials and a meta-analysis (in which he and Berry are involved) also suggest that the DE combination is “an interesting and reasonable option for patients with no thromboembolic history“, notes Eymard. Berry agrees that the current evidence supports the use of the combination, but adds that when he uses estramustine, he fully anticoagulates with warfarin.
Jane Bradbury http://oncology.thelancet.com Vol 8 June 2007