Bisplatinates, a New Class of Platinum-Based Anti-Tumor Drugs, Demonstrates Potent Anti-Tumor Activity and Ability to Overcome Resistance to Currently Available Platinum-Based Agents

Seattle-based Cell Therapeutics, Inc, a biopharmaceutical company committed to developing an integrated portfolio of oncology products, today announced that its new class of platinum-based anti-tumor compounds, termed bis-platinates, demonstrated a stronger anti-tumor potency and activity compared to currently available platinum-based compounds as well as the ability to overcome cisplatin-resistance in cancer cell lines.

The results were presented in a paper titled "Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile," by Laura Gatti et al. that was published in the online edition of the journal Molecular Pharmaceutics. Platinum-based compounds, such as cisplatin and oxaliplatin, are the cornerstone in the treatment of testicular, ovarian, colorectal, lung and other cancers but their effectiveness is limited by the relatively low therapeutic ratio, the ratio of the maximally tolerated dose of the drug to the effective dose, and the frequent occurrence of drug resistance leading to cancer recurrence. The novel bis-platinum compounds represent a completely new class of platinum-based drugs called bisplatinates.

The bis-platinum based compounds, unlike the currently approved platinum-based compounds, contain two platinum atoms and work by binding to and damaging both strands of DNA making it much more difficult for cancer cells to repair the damage. The research demonstrated through cancer cell assays and animal tumor models that the bis-platinum complexes exhibited greater cytotoxic potency and anti-tumor effect compared to cisplatin and oxaliplatin.

There was more than a 200-fold increase in percent accumulation in tumor cells of the bisplatinum compounds compared to cisplatin and oxaliplatin. The bisplatinates were substantially more active against human tumors grown in an immunodeficient preclinical model than the standard palatinate compounds, oxaliplatin, carboplatin and cisplatin. Furthermore, the bis-platinum compounds demonstrated the ability to overcome tumor resistance to cisplatin mediated by DNA mismatch repair defects. The complexes showed marked anti-tumor efficacy in platinum refractory tumors, with significant activity in terms of tumor growth inhibition and tumor growth delay.

"Platinum-based compounds are cornerstone agents in the treatment of very common cancers such as cancers of the lung, colon, and ovary and are also widely used in other gynecological-tumors, testicular cancers, and cancers of the esophagus, head and neck. They are increasingly being used for salvage therapy in lymphoma. However, resistance to palatinate compounds is common. The current results are encouraging as they demonstrate that the bisplatinates are not only more effective in human tumor models than the current agents, but also capable of overcoming some forms of palatinate resistance," said Jack Singer, M.D., Chief Medical Officer of CTI.

For more information:
Gatti L, Perego P, Leone R, Apostoli P, Carenini N, et al. Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile. Mol Pharm. 2009 Nov 17. [Epub ahead of print]

Also see:
Bisplatinates, a New Class of Platinum-Based Anti-Tumor Drugs, Demonstrates Potent Anti-Tumor Activity

A Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms

Research by Dr. Francois Delhommeau MD, and his team at the Saint-Antoine Hospital, Paris, France (Hôpital Saint Antoine, Service d’hématologie, 184, rue du Faubourg Saint Antoine, 75012 Paris) on treatment advances in leukemia and lymphoma, presented as late-breaking news during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA,(December 6 – 9, 2008), led to the discovery of a new tumor suppressor gene called TET2 (Ten-Eleven Translocation–2).

Because TET2 is altered in 14 percent of patients with myeloproliferative disorders, the discovery provides scientists with a greater understanding of the underlying biology of these conditions, as well as a potential target for the development of future treatments.

All blood cells start out as hematopoietic, or blood-forming, stem cells and have the potential to become mature red blood cells, white blood cells, or platelets. Myeloproliferative disorders develop when the DNA of a stem cell is altered in the bone marrow, causing the overproduction of some blood cells.

Previous research has detected mutations in other genes– JAK2 and MPL – in the blood stem cells of patients with myeloproliferative disorders. These JAK2 and MPL defects cause the overproduction of mature malignant blood cells, but multiple lines of evidence suggest that these are not the only molecular lesions responsible for abnormalities in the stem cell in these disorders. Greater analysis of blood cell development in myeloproliferative disorders with the JAK2 V617F mutation led researchers to identify two subsets of patients. The first subset of patients (85 percent) had an overproduction of malignant cells mainly dependent on the late stages of blood cell differentiation, far downstream from the stem cell. In contrast, a second subset of patients (15 percent) had an early expansion of very immature malignant progenitor cells, close to the stem cell.

Researchers then hypothesized that the second subset of patients had a pre-existent molecular defect able to promote the early expansion of the malignant cells. With high-resolution arrays, researchers were able to identify one single gene, TET2, which belongs to a family of three genes of unknown function.

Researchers then further analyzed cells in five patients with TET2 mutations, which demonstrated that TET2 defects target hematopoietic stem cells. Moreover, they show that in these five patients TET2 inactivation precedes the JAK2 V617F mutation, suggesting that this new molecular lesion could be an early event in cancer stem cell formation.

To further test these findings, researchers sequenced TET2 in 181 unselected JAK2 V617F patients with myeloproliferative disorders. TET2 mutations were found in 25 of the 181 patients, resulting in an overall 14 percent frequency.

For more information, read:

• Delhommeau F, Dupont S, James C, Masse A, et al. TET2 Is a Novel Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms: Identification of a Pre-JAK2 V617F Event. (Late-Breaking Abstracts) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract LBA-3

Also read PubMed abstracts:

• Delhommeau F, Pisani DF, James C., et al. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci. 2006 Dec;63(24):2939-53
• Delhommeau F, Dupont S, Tonetti C, Massé A. et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007 Jan 1;109(1):71-7. Epub 2006 Sep 5.