December 11 2008 post. It sounds like the name of a new videogame or a deadly disease, but Zalypsis is actually a newly-discovered (by a University of Salamanca research team) potent anti-myeloma substance, a new synthetic alkaloid related to various compounds isolated mainly from marine sponges. You can almost envision the excitement of these Spanish researchers when they declare that Zalypsis is the most active antimyeloma agent tested in our laboratory (see study abstract: http://tinyurl.com/59faqe). Further on, in the full study, they write that Zalypsis is at least 10 times more potent than any of the antimyeloma agents we have tested so far. 10 times…wow.
Okay, I will now launch into the full study, provided by Sherlock (grazie!) and pointed out to me by a blog reader (another grazie!).
Zalypsis was tested on nine different myeloma cell lines and bone marrow samples from myeloma patients. In every single case, including two cases of plasma cell leukaemia, it killed the cancerous cells. Apoptosis…
As for Zalypsis and healthy cells, I thought it would be good to copy the relevant paragraph: Upon analyzing the efficacy of a new agent a mandatory experiment is to investigate its toxicity in normal cells. These experiments are usually conducted on normal peripheral blood samples. We have developed an ex vivo technique that allows to simultaneously analyze the cell death induced by a particular agent both on the malignant cells and the residual BM cells. Now, for the first time using multiparametric flow cytometry, we have analyzed the action of Zalypsis on the cell subset that mainly corresponds to the normal stem cells (CD34+, CD38-, CD33-) and have seen that Zalypsis does not affect this cell population although is toxic for the more mature myeloid population. So, good news. Too bad that Zalypsis, from what I gather, is not effective against the myeloma stem cell population…
Another important discovery: Zalypsis inhibited IL-6 and eliminated the protection offered to myeloma cells in the bone marrow microenvironment, which confers protection to myeloma cells through their adhesion or through the production of several cytokines such as IL-6 […]. Precisely. Excellent.
Zalypsis was also found to work in synergy with and increase the efficacy of Dexamethasone, Melphalan, Doxorubicin, Bortezomib and Lenalidomide, which are all conventional drugs used to treat myeloma. In particular, it was effective when combined with Dex and Lenalidomide. It also increased tumour-killing p53 levels in most cell lines, more effectively and strongly than doxorubicin.
And remember our “friend,” Bcl-x? Well, Zalypsis also inhibited Bcl-x (but not Bcl-2; well, we can’t have everything…).
According to the researchers, Zalypsis has been found to have an acceptable toxicity profile. In this particular “Blood” study, they tested Zalypsis on three groups of mice (one control group and two groups receiving different Zalypsis doses) and found that no significant systemic toxicity was associated with Zalypsis treatment, and only a slight weight loss (around 10% of body weight as compared to the controls) was observed with the highest of the doses. Nevertheless, an important local toxicity was caused at the site of injection of Zalypsis with ulcerations and necrosis of the tail in some of the mice. Ok, we aren’t mice and don’t have tails, but should we be concerned?
The Phase I clinical trial (http://tinyurl.com/6yud2r) has ended. According to an October 2008 PharmaMar (the company marketing Zalypsis) press release (http://tinyurl.com/5tr5fu), […] the safety of Zalypsis in 37 patients with solid tumors or lymphoma was evaluated. The trial shows a good safety profile of the drug, which enables the continuation of its clinical development.
The press release informs us that Zalypsis was also tested in some childhood malignancies: The most significant results in in vitro tests were obtained in neuroblastoma and rhabdomyosarcoma cell lines. The evaluation of the compound in animal models also showed significant results, especially in the activity in rhabdomyosarcoma.
So, to sum up, Zalypsis was effective on myeloma cell lines that had become resistant to conventional chemo drugs. It worked synergistically with several anti-myeloma drugs, especially Lenalidomide and Dexamethasone. It also profoundly affected the growth of plasmacytomas in mice. The list goes on. Yes, it sounds like a very promising substance to me.
Study’s conclusion. The action of Zalypsis in MM therefore involves several interlaced pathways that move into an apoptotic response, likely initiated by direct DNA damage. These pathways may include p53-dependent and p53–independent routes that by acting on caspases and other apoptotic signalling pathways hamper MM cell proliferation and trigger apoptosis. The potent antimyeloma action of Zalypsis, together with the particular mechanism of action of this compound strongly supports the initiation of clinical studies in MM patients.