To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusion is critical for cancer cell survival. Pantoprazole, a commonly employed proton pump inhibitor increases apoptotic cell death in cancer cells contrasting with normal gastric mucosal cells which showed resistance to pantoprazole-induced apoptosis. Pantoprazole also inhibited tumorigenesis in vivo. This study and earlier studies showing that proton pump inhibitors can increase the anti-cancer efficacy of common cytotoxic agents will hopefully prompt further clinical studies and may eventually lead to new indications being approved for this class.

The proton pump inhibitor class of drugs is one of the most lucrative drug categories generating $12 billion in annual world-wide sales. However this market been exposed to both generic and OTC competition. In particular Prilosec (omeprazole), which in 2001 was the world's second-biggest selling drug with revenues of $5.7 billion, went off-patent in 2002. In 2003 the FDA approved its switch from a branded pharmaceutical to an over-the-counter drug signalling a decline in Prilosec sales for AstraZeneca. Consequently the dynamics of the proton-pump inhibitor market will change in the near and medium term and companies such as AstraZeneca, Tap, Wyeth, Eisai, and Janssens with proton pump inhibitors in their portfolio are fighting to find novel ways of maintaining revenue. While their sales of Prilosec continue to fall, AstraZeneca continues to push its other proton-pump inhibitor Nexium. Nexium achieved global annual sales of $3.3 billion in 2003, which were up 62% compared with 2002 (for an in depth evaluation of the proton pump inhibitor class click here).

One strategy for leveraging proton pump inhibitors has been the identification of new indications. For example, in November 2004 Nexium was approved for reducing the risk of gastric ulcers developing among patients on continuous therapy with nonsteroidal anti-inflammatory drugs. Two recent studies have suggested that proton pump inhibitors could be of specific use in patients with cancer and this could lead to further new indications for this class.

Despite the advent of innovative agents in recent years, cytotoxic agents still remain the mainstay of cancer treatment due to high unmet needs in the disease. Because the oral and gastrointestinal mucosa is often significantly damaged by cancer therapy, management of these problems is an important challenge for oncologists. Such treatment complications are generally not severe or life threatening, but they can result in both treatment delays and dose reductions in potentially curative regimens. Numerous therapeutic approaches have been evaluated as prophylaxis or treatment for mucosal damage in patients undergoing cancer therapy. The results of large-scale, placebo-controlled, comparative trials demonstrate that administration of a proton pump inhibitor can provide both significant symptom relief and prophylaxis against upper gastrointestinal ulceration in patients receiving cancer chemotherapy. Head-to-head studies comparing different proton pump inhibitor in patients receiving chemotherapy have not been published.

Last year a study was published in J Natl Cancer Inst suggesting that in addition to providing symptomatic and gastroprotective relief to cancer patients under chemotherapy, proton pump inhibitors may be able to improve therapeutic efficacy. A variety of chemotherapies are available to oncologists and these generally reduce the rate of tumor progression. However intrinsic or acquired tumor-mediated drug resistance is a major clinical obstacle that can result in the lack of tumor responsiveness in patients undergoing treatment. The over-expression of efflux proteins such as p-glycoprotein are well recognized as contributing to the drug resistance process due to their ability to pump cytotoxic therapies out of the cell. In addition to being actively extruded from cancer cells, chemotherapeutic agents encounter passive resistance on entering the cells due in part to increased acidification of extracellular compartments. In last year's study Luciani et al reported that omeprazole, esomeprazole and pantoprazole all sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine. This was related to a marked increase in the cytoplasmic retention of the cytotoxic drugs. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin.

More recently researchers have shown that in addition to facilitating the entry of chemotherapeutic agents into cancer cells, proton pump inhibitors may also make these cells more susceptible to apoptosis. In the December 2004 edition of Clin Cancer Res, Yeo et al reports that pantoprazole, a commonly employed proton pump inhibitor increases apoptotic cell death in gastric cancer cells contrasting with normal gastric mucosal cells which showed resistance to pantoprazole-induced apoptosis. Pantoprazole also limited the growth of tumors in vivo.

The H+/K+-ATPase of gastric parietal cells is responsible for gastric acidification and is the target for proton pump inhibitors. To survive in an ischemic microenvironment with a lower extracellular pH (due to high levels of glycolysis), the ability to up-regulate proton extrusion is critical for cancer cell survival and this ion exchanger may therefore also plays a role in tumor progression. Indeed Yeo et al reported that cancer cells were characterized by an over-expression of the alpha subunit of H+/K+-ATPase both within the cytoplasm and plasma membrane and a reduced sensitivity to acidification. Inhibition of H+/K+-ATPase activity pantoprazole reduced the viability of gastric cancer cell lines in an acid environment. Further investigation demonstrated that pantoprazole was able to increase apoptosis in the cancerous cells and this was replicated under in vivo conditions where the growth of gastric cancer cells was dramatically reduced. Pantoprazole failed to stimulate apoptosis in non-cancerous gastric cells in vitro and this coupled with the well documented safety profile of the proton pump inhibitors suggests that the cytotoxic effects pantoprazole are restricted to cancer cells.

In summary therefore the efficacy of proton pump inhibitors in cancer patients may extend past symptomatic and gastroprotective relief during chemotherapy, and this class may in addition slow tumor growth per se and also enhance the efficacy of chemotherapy. If these findings can be replicated under clinical conditions, companies may wish to file NDAs for the use of proton pump inhibitors in combination with chemotherapies. Of additional interest, excessive gastric secretion is associated with erosive esophagitis which can lead to esophageal cancer. Proton pump inhibitors are indicated for the short-term treatment of erosive esophagitis however studies investigating the chemopreventive activity of long-term treatment in at-risk individuals may be warranted.

Entry date Thursday, January 27, 2005