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Nuvilex, Inc. Cell Encapsulation Could Mimic Combination Chemotherapy

Nuvilex, Inc. Cell Encapsulation Could Mimic Combination Chemotherapy

Written by ι Stock Market Media Group Staff — May 15, 2013

Nuvilex, Inc. (OTCQB: NVLX) has had its living cell encapsulation or “Cell-in-a-Box” technology tested again and again, and each time it has proven it can do exactly what it’s intended to do.  To date, the proprietary technology has more than impressed and continuously returns remarkable data after each study.  In a study not yet discussed, “Cell-in-a-Box” was used to enclose cells that activate more than one anticancer drug simultaneously.  This is a form of combination chemotherapy, and using the cell encapsulation technology to achieve the simultaneous reaction has been validated in a preclinical breast cancer study that took place in Germany.

What is Combination Chemotherapy

First a little background on combination chemotherapy.  It is the use of two or more drugs in parallel or in close sequence to one another during a round of chemotherapy, and this approach is often used to treat various types of cancer, particularly when the disease is at an advanced stage.  Combination chemotherapy regimens are often used for cancers that are not responsive to treatment by surgery, radiation, or those that do not (or no longer) respond to treatment with single drugs.

The drugs used in combination chemotherapy regimens are usually used together because each of the drugs in combination “kill” cancer cells in a different way.  Therefore, by combining such drugs, it is believed that it’s more difficult for the cancer cells to become resistant to treatment over time as they might if only a single drug were to be used.  In addition, the drugs used together in combination usually have differences in their side effect (toxicity) profiles.  In this way, the combined toxicities may be less likely to cause reductions in the doses of the constituent components of the combination (thus reducing their effectiveness) than might be the case if the side effect profiles (toxicities) of the drugs were very similar.

Cell Encapsulation Involved in Gene Therapy

Gene therapy as a treatment for diseases has been under investigation for many years.  Some of the first clinical trials using gene therapy were directed towards the treatment of different cancers.  Nuvilex’s “Cell-in-a-Box” has taken part in the growing list of studies trying to conquer this complex therapy.  In doing so, it once again showed off what makes it a go-to technology for treatments that involve “targeting” a tumor and protecting the encapsulated drug-activating cells from attack by the body’s immune system while they’re at work inside the body.

In the industry’s early trials, “suicide genes” were used that encode for (“produce”) enzymes that convert inactive prodrugs into their “tumor-killing” forms in a process known as “gene-directed enzyme prodrug therapy,” or GDEPT.  By 2011, more than 100 clinical trials had involved the use of a single gene alone, from herpes simplex virus, which encodes for the enzyme thymidine kinase.   This was the first suicide gene tried for cancer therapy (brain tumors) in the early 1990s. 

Some of the reasons that GDEPT for cancer treatment has not progressed more rapidly include:

•  Relatively short duration of activity of the suicide genes that are employed.

•  Poor rates of “transfer” of the genes from the viruses that are used as a source of the genes.

More recently, an alternative means of using GDEPT to treat tumors, rather than using viruses directly, is to use genetically-modified cells that contain high activities of prodrug-activating enzymes that are implanted near, or within the tumor.   Then, the particular prodrug associated with the enzyme that was “amplified” in the cells is administered.  The implanted cells must be protected from attack by the recipient’s immune system and must remain at the site where they’re needed, specifically, within or near the tumor.  Both of these requirements are fully satisfied by Nuvilex’s cellulose-based cell encapsulation technology.

Another major advantage for the use of Nuvilex’s cell encapsulation as part of GDEPT for cancer is that the prodrug can be converted into its cancer-killing form in a sustained manner because the cells are constrained within the capsules and cannot divide.  This protects the cells within the capsules from damage from the activated prodrug because many cancer prodrugs, after activation, only kill dividing cells.

Nuvilex’s treatment for advanced, inoperable pancreatic cancer is an excellent example of the use of GDEPT for the treatment of one of the deadliest forms of the disease.  In this treatment, cells with elevated levels of an enzyme known as CYP2B1, are encapsulated and then used in combination with the long used anticancer drug, ifosfamide.  Ifosfamide is converted into its cancer-killing form by CYP2B1.

In preclinical studies where cell encapsulation was used for combination chemotherapy of mammary (breast) cancer, two well characterized suicide genes were used as part of GDEPT for the treatment of two types of mammary cancer in mice.  The genes employed in the study amplified the activities of two different drug-activating enzymes; these enzymes were:

1.  CYP2B1

2.  Cytosine Deaminase

Anyone following Nuvilex is familiar with CYP2B1 because of its use in the company’s pancreatic cancer trials, and knows it’s well known to convert the prodrug ifosfamide into its cancer-killing form.  Meanwhile cytosine deaminase converts the prodrug 5-fluorocytosine into the widely used anticancer drug 5-fluoruracil.

Ifosfamide is converted by CYP2B1 into the substances phosphoramide mustard and acrolein.  These two substances “alkylate” DNA and proteins making the “copying” of DNA impossible and this prevents cells from dividing, whereas, the 5-fluorouracil produced from the action of cytosine deaminase on 5-fluorocytosine enters cells and prevents the synthesis of new DNA (and RNA) necessary for cell division and the production of new cells, and in this case, tumor cells.

Let the Study Begin

Let’s go blow by blow and dig into the results of this study.  CRFK feline kidney cells were developed with elevated activities of the enzymes CYP2B1 and cytosine deaminase in the same cells.  Then the cells were encapsulated using Nuvilex’s unique encapsulation technology.

The two types of tumors used in the study were mouse mammary tumors designated as TS/A and GR.  Both the TS/A and GR tumors were allowed to grow in the mice to sizes of 4-5 mm in diameter (after 10 days) and 7-9 mm in diameter (after 42 days), respectively.  The tumors were then injected with 70-80 capsules containing cells with elevated levels of the CYP2B1 and cytosine deaminase enzymes.

How Did “Cell-in-a-Box” Perform

Next, the prodrugs ifosfamide and 5-fluorocytosine were administered, either each alone or as a two-drug combination, at doses that were non-toxic to the mice, every 3 days throughout the study.  The results of the study showed that, when GDEPT was used against these two models of mouse mammary cancer:

•  The antitumor effect of the CYP2B1/ifosfamide treatment alone was more effective than the cytosine deaminase/5-fluorocytosine treatment against TS/A tumors, but both were equally effective against GR tumors.

•  But, most importantly, when the combination GDEPT (CYP2B1/ifosfamide plus cytosine deaminase/5-fluorocytosine) was used, the tumor-killing effect was by far the greatest for both tumor models and even led to one animal being completely tumor-free.

Nuvilex COO, Dr. Gerry Crabtree says of the results, “It is possible that cell encapsulation plus GDEPT similar to that used in this study could also find a role in the combination chemotherapy treatment of breast cancer in humans.

In other preclinical studies using our cell encapsulation technology, we saw that cells with high levels of CYP2B1 were used with the drug cyclophosphamide to successfully treat spontaneously-occurring mammary tumors in dogs.”

Dr. Crabtree said that cyclophosphamide is converted to its cancer-killing form by the enzyme CYP2B1, the same enzyme used to activate the cancer drug ifosfamide in the aforementioned study and in the clinical trials in pancreatic cancer.  Both cyclophosphamide and 5-fluorouracil are part of several combination chemotherapy regimens that are commonly used to treat breast cancer in humans, so the COO finds himself asking:

“Could the cell encapsulation plus a similar combination GDEPT in which ifosfamide is replaced by cyclophosphamide also be applicable to the treatment of breast cancer in humans, and if so could such a cell encapsulation plus combination GDEPT replace the cyclophosphamide plus 5-fluorouracil combination that is part of many combination chemotherapy regimens for the treatment of breast cancer?  Given the previous clinical results of the use of cell encapsulation with a single cancer prodrug where the cancer-killing effects of the activated prodrug was optimized, it is not inconceivable that by using cell encapsulation with two prodrugs, similar optimization might be realized with combination chemotherapies against breast cancer.”

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