Prodrax® Fact Sheet

What is Prodrax?

Cytotoxic compounds are designed to kill tumor cells, but most cancer drugs in common use today show little discrimination between cancer cells and rapidly-dividing normal cells. The severe side-effects associated with anticancer therapy result primarily from this indiscriminate attack on normal cells. It would be preferable to use treatments which are much more selective. The Access Prodrax program provides a way of chemically altering a cytotoxic drug, so that it is relatively harmless in circulation, but in the tumor environment, the drug is activated; and the cytotoxic drug is able to exert its cell-killing effect selectively on tumor cells.

The concept of chemically altering a drug for later activation at specific sites in the body is not new; such compounds are called prodrugs. Another of Access’ development compounds, ProLindac, also uses a prodrug approach to deliver highly cytotoxic platinum compounds to tumors. The Prodrax program uses a novel N-oxide approach, where an oxygen atom is bound to a nitrogen atom to temporarily disable the cytotoxic properties of the anticancer compound. The N-oxide also serves to enhance the ability of the compound to traverse biological membranes, ensuring that the prodrug is able to get to distant tumor cells more easily. The oxygen atom is stripped away in areas of the body that have a very low oxygen levels, so-called hypoxic regions. Once the oxygen atom is stripped away, the compound is transformed to its native cytotoxic state.

Hypoxia in Tumors

Because of their well-established blood supply, normal tissues generally receive an adequate amount of oxygen. In fast-growing tumors, the growth of new blood vessels is often outpaced by tumor growth, leaving areas of tumors deficient in oxygen, or hypoxic. While hypoxia in normal tissues has a detrimental effect on tissue function, tumors appear to thrive on this state. Tumor hypoxia has been associated with tumor propagation and progression; the state of hypoxia provides the tumor with a way to resist conventional cancer therapy. The advantage of the Prodrax approach is that it is specifically in the hypoxic regions of a tumor that the oxygen atom temporarily deactivating Prodrax is stripped away to release the cytotoxic drug.

As shown in the diagram, hypoxia occurs in regions which are furthest from a blood supply. To kill hypoxic tumor cells, currently-used cytotoxic drugs typically have to diffuse through many layers of normally-oxygenated cells. As a result, by the time these drugs reach the hypoxic region of the tumor, the concentration of the drugs in the hypoxic regions is often inadequate to kill the tumor cells. Furthermore, radiation therapy is much less effective in hypoxic regions as radiation needs oxygen to form the free-radicals which kill tumor cells.

Solid tumors can consist of up to 50% hypoxic areas, and many standard drugs and treatment regimens are incapable of exerting a meaningful anti-tumor effect in these regions.

The targeting ability of a Prodrax compound is illustrated below. By using a staining technique, the location of a Prodrax molecule in the tumor can be readily demonstrated. Spheres of tumor cells (HT29 colon spheroid tumor cells) are incubated either with a Prodrax molecule (shown on the right) or the its metabolite – with the oxygen atom already removed (shown on the left). The tumor spheres receive oxygen from their surroundings, so the cells close to the surface are normally oxygenated, while the cells closer to the center are hypoxic. The purple florescence shows the distribution of molecules within tumor spheres in each case.

(from studies conducted at the University of Bradford, UK)

The Prodrax compound appears primarily in the hypoxic region (shown on the right), having diffused through the normally oxygenated region unchanged. By comparison, the administration of the active form of the Prodrax molecule (without the N-oxide. Shown on the left) attacks the most easily accessible tumor cells, the normally oxygenated cells at the surface, leaving little drug available to reach and attack the cells in the hypoxic region.

Because it is inactive in normally oxygenated tissues, Prodrax molecules should potentially provide a superior safety profile compared to regular chemotherapeutic agents. Moreover, because Prodrax metabolites are capable of initiating tumor apoptosis by several different mechanisms, it is anticipated that Prodrax could have a broad spectrum of activity against tumors, working in synergy with many drugs that are highly effective in the normally oxygenated zones of tumors, but are unable to have significant impact in the hypoxic regions.

Activated Prodrax Molecules Attack Tumor DNA

The cytotoxic form of Prodrax molecules binds to the DNA in tumor cells and interrupts their cell cycle through three mechanisms:

• Intercalation
• Alkylation
• Topoisomerase II Inhibition

Intercalation occurs when the size and shape of these molecules enables them to insert themselves in the DNA helix; alkylation means that a molecule can form a chemical bond to attach itself to DNA. The active form of Prodrax molecules are also topoisomerase II inhibitors (topoisomerase II is an enzyme that repairs damaged DNA, that may occur, for example, following radiotherapy). Unlike most other anticancer compounds, Prodrax molecules can be effective through multiple mechanisms of action and therefore have the potential to overcome tumor drug resistance. The unique characteristics of Prodrax molecules therefore provide them the opportunity to attack cancer stem cells which may elude other chemotherapeutic agents.