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

No Improvement in Local Tumor Response by adding Oxaliplatin to Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer

A large, multicenter Italian study has found that adding oxaliplatin (Eloxatin, Sanofi-Aventis) to standard preoperative radiochemotherapy in patients with locally advanced rectal cancer does not improve tumor shrinkage.

However, preliminary and exploratory data from the study, presented on Saturday, May 30, 2009 by Carlo Aschele, MD, PhD, E.O. Ospedali Galliera, (Mura delle Cappuccine, 1416128 Genova (Ligurie), Italy, Phone +39 010 5 6321) during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida, suggest that it may reduce the number of distant metastases.

Chemotherapy and radiation are often administered before surgery for rectal cancer to shrink the tumor and make it easier to remove. Previous results from this study showed that although adding oxaliplatin to standard chemotherapy increased some side effects, especially diarrhea, it did not affect the ability to deliver the full course of radiation therapy or to perform surgery. Oxaliplatin has been found effective and is commonly used in patients with more advanced colon and rectal cancer.

In this phase III trial, 747 patients with locally advanced rectal cancer were randomized to receive standard preoperative chemoradiotherapy or the standard plus oxaliplatin. Researchers found no significant difference between the two groups in terms of tumor reduction: 16 percent of patients in both groups had no tumor present at the time of surgery, and 29 percent in the oxaliplatin group had mildly invasive tumors (T1 or T2) without nodal involvement, compared with 30 percent in the control group. There was also no significant difference in the number of patients who had cancer in the lymph nodes (27 percent in the oxaliplatin group versus 25 percent in the control group). Consistently, the proportions of patients who could have conservative surgery were similar between the two arms.

In an unplanned analysis, when looking at intra-abdominal disease spread at the time of surgical removal of the primary tumor, only 0.5 percent of patients in the oxaliplatin group (2 patients) had distant metastases, versus 3 percent in the control group (11 patients), a difference that was statistically significant.

“Although adding oxaliplatin to the current standard of care did not improve tumor response rates, we found this course of treatment was associated with a reduced number of early distant metastases in the abdomen in a very small number of patients,” said Carlo Aschele, MD, PhD, attending physician and lead clinician in Colorectal/Gastrointestinal Cancer in the Department of Medical Oncology and Cancer Prevention at E.O. Ospedali Galliera in Genoa, Italy, and the study’s first author.

“Although the numbers are very small and the analysis of distant metastases was unplanned and exploratory, the difference is significant and indicates that the lack of an effect on local tumor shrinkage does not necessarily imply a lack of effect on micrometastases at distant sites. Longer follow-up is necessary to assess whether treatment with oxaliplatin will have an effect on recurrence rates or survival.”

Note: This article contains updated data not published in the original ASCO 2009 abstract

For more information:

• Aschele C, Pinto C, Cordio S, Rosati G, Tagliagambe A, Artale S, Rosetti P, Lonardi S, Boni L, Cionini L. Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. Abstract: CRA4008
• American Society of Clinical Oncology (ASCO)

New studies answer key questions about the treatment of gastrointestinal cancers

Findings from a number of large clinical trials of new treatment regimens for gastrointestinal cancers were released today at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held in Orlando, May 29 - June 2, 2009 and will be highlighted in Onco’Zine – The international Cancer Blog.

“The studies presented today answer many important questions about the best care for people with gastrointestinal cancers,” said Nicholas Petrelli, MD, medical director of the Helen F. Graham Cancer Center in Wilmington, Delaware. “These large, conclusive trials tell us what works, and importantly, tell us what doesn’t work. Some settle long-time debates in the field, others demonstrate that the current standard of care is actually superior to experimental treatments, and others will allow patients to avoid unnecessary side effects or surgery.”

The results presented include:

• First-ever data on bevacizumab as adjuvant therapy finds no benefit in colon cancer: A phase III trial finds that adding the targeted therapy bevacizumab (Avastin, Roche), to standard adjuvant chemotherapy did not improve disease free survival for patients with locally advanced colon cancer.
• Surgery unnecessary for majority of patients with advanced colorectal cancer: Most patients with metastatic colorectal cancer can safely avoid surgery on their primary tumors.
• A trial compares common adjuvant treatments for pancreatic cancer: A phase III trial comparing the adjuvant treatments most commonly used for pancreatic cancer in the United States and Europe, gemcitabine (Gemzar, Eli Lilly and Company) and 5-FU/FA, respectively, found that there is no difference in survival between the two regimens, though gemcitabine was associated with fewer side effects.
• The largest study to date on anal cancer supports the current standard: A phase III study finds that the current standard of care for anal cancer should not be changed, and that ongoing maintenance therapy after initial treatment is not effective.
• Oxaliplatin does not improve outcomes for rectal cancer: Adding oxaliplatin (Eloxatin, Sanofi-Aventis) to standard treatment in patients with locally advanced rectal cancer does not improve tumor response. However, a preliminary analysis seems to suggests that the treatment may reduce distant metastases.

For more information:

• American Society of Clinical Oncology
• 2009 ASCO annual meeting abstracts

Reference:

• Medical-Oncology (at Boomja.com)