Intralesion & Curaderm Compared Treatment of Large Skin Cancers

Intralesion and Curaderm BEC5 Topical Combination Therapies of Solasodine Rhamnosly Glycosides Derived from Eggplant or Devil’s Apple Result in Rapid Removal of Large Skin Cancers. Method of Treatment Compared.
(International Jounral of Cinical Medicince, 2012, 3, 115-124; dpi:10.4236/ijcm.2012.32024 Published Online March 2012 (http://www.SciRP.org/journal/ijcm))

Click here to download your a copy of a Curaderm BEC5 article printed in International Journal of Clinical Medicine in March 2012

Below is this article written in laymen’s terms.

Abstract (The dictionary says: – synopsis, précis, résumé, outline,abridgment, digest, summation; wrap-up)
Solasodine rhamnosyl glycosides (SRGs) are chemotherapeutic agents for the treatment of cancer. SRGs in a cream formulation like in CuradermBEC5 is very effective for the treatment of non-melanoma skin cancers with excellent cosmetic end results.

Intralesion injection of SRGs will successfully destroy very large tumours in animals without any clinical or adverse effects. SRGs does this by apoptosis (is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage,nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation).

In this study, it is shown that small to large basal cell carcinomas are effectively treated only with topical application of CuradermBEC5. Here it is reported for the first time that combination of intralesion SRG injection and topical application with CuradermBEC5 in humans reduces the treatment time period by more than half when compared with topical application as the sole treatment. Two intralesion injections of very low doses of SRGs rapidly and effectively remove a large melanoma on a horse. If rapid removal of large troublesome skin cancers is required then this can be achieved by intralesion and topical treatments. Intralesion or combination therapy with SRGs may have some applications for melanomas in situations such as lentigo maligna (Lentiginous melanoma on sun-damaged skin).

1. Introduction
Antimitotic chemotherapeutic agents appear to affect fast growing cells by killing such the cells as they divide. When the cells are not dividing the antimitotic chemotherapeutic agents have very small effect on these cells. Consequently, when treating cancer cells with existing antimitotic chemotherapeutic agents it is a long and repetitive treatments process. Also, certain cancers have developed drug resistances which complicate antimitotic therapy. The side effects of antimitotic chemotherapy are also well know.

Solasodine rhamnosyl glycosides (SGRs) are very promising antineoplastics (chemotherapy treatment). Oral (by mouth), intravenous (Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein), intraperitoneal (Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity)) and intralesion (Intralesional therapy implies injecting a drug directly into the skin lesion) studies with these glycoalkaloids have been described  as promising. Many studies have reported the high antineoplastic (chemotherapy treatment) efficacy with a low dose of solamargine and solasonine and a constant mixture of these glycoalkaloids (Curaderm BEC5). Unlike other antimitotic drugs, Curaderm BEC5 has it individual glycoalkaloids, solamargine and solasonine and are not antimitotic in their actions. Curaderm BEC5 induces apoptosis (is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage,nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation) in cancer cells by increasing the rate of the external death receptors, such as the tumour necrosis factor receptor (a tumor necrosis factor receptor (TNFR), or death receptor, is a trimeric cytokine receptor that binds tumor necrosis factors (TNF). The receptor cooperates with an adaptor protein (such as TRADD, TRAF, RIP), which is important in determining the outcome of the response (e.g. apoptosis, inflammation)).

Curaderm BEC5 also enhances the intrinsic ratio (an intrinsic property is an essential or inherent property of a system or of a material itself or within. It is independent of how much of the material is present and is independent of the form the material, e.g., one large piece or a collection of smaller pieces. Intrinsic properties are dependent mainly on the chemical composition or structure of the material) of Bax to Bcl-2 by up-regulating Bax and down-regulating Bcl-2 and Bcl-xL expressions. These effects result in activation of Caspase –8, –9 and –3 in cancer cells, indicating that Curaderm BEC5 triggers extrinsic and intrinsic apoptotic pathways in cancer cells – so this part is hard to explain,  lets just say it effectively attacks the cancer cells and the science proves it.

Solamargine, the main component of Curaderm BEC5, also kills cancer cells by oncosis (ischemic cell death, or Oncosis, is a form of accidental, or passive cell death that is oftentimes considered a lethal injury. The process is characterized by mitochondrial swelling,cytoplasm vacuolization, and swelling of the nucleus and cytoplasm). After interaction of solamargine with cancer cells, the cell shape and volume changes. The cells get blebs on the membrane (in cell biology, a bleb is an irregular bulge in the plasma membrane of a cell caused by localized decoupling of the cytoskeleton from the plasma membrane. Blebbing is the term used to describe the formation of blebs and is sometimes referred to as zeiosis), the mitochondria swell (in cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometer (μm) in diameter), the contents of the nuclei clump (in cell biology, the nucleus is a membrane-enclosedorganelle found in eukaryotic cells. It contains most of the cell’s genetic material, organized as multiple long linear DNAmolecules in complex with a large variety of proteins, such as histones, to form chromosomes) and the cells die. It has been proposed that apoptosis and oncosis share certain mechanisms and alterations within the cell before they die by bursting.

At low concentrations solamargine kills cancer cells by apoptosis and at higher doses, solamargine kills cancer cells by oncosis, and both types of cell death are induced by intermediate concentrations of solamargine.

It has recently been shown that, in addition to causing apoptosis in cancer cells, intralesion administration (Intralesional therapy implies injecting a drug directly into the skin lesion) of Curaderm BEC5 also stimulates a lasting immunity against cancer.

Intravenous administrations (Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity)) of drugs pose a number of serious limitations including toxicity to body organs. Because of the dilution effect of the drug within the vascular system (the circulatory system is an organ system that passes nutrients (such as amino acids, electrolytes and lymph), gases, hormones, bloodcells, etc. to and from cells in the body to help fight diseases, stabilize body temperature and pH, and to maintain homeostasis) and the pharmacokinetics (Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. The substances of interest include pharmaceutical agents, hormones, nutrients, and toxins) of the drug by numerous body organs, a relatively high dose of the drug has to be administered frequently for it to have a therapeutic effect on the targeted cancer cells and this high dose may result in serious toxicological effects.

Intravenous doses are dependent on body weight or volume. It was shown that intralesion injection of BEC is far superior to i.v. injection if the targeted lesion being treated is rapidly and specifically degraded by the chemotherapeutic agent. Intralesion injections of very low doses of Curaderm BEC5 into large chondrosarcomas and squamous cell carcinomas in ani-mals completely eliminate these tumours. The required dose of intralesion injections are tumour weight dependent and not body weight dependent and are 100 times lower than for i.v. infusions.

Curaderm BEC5 is a topical cream which contains a mix-ture of solasodine glycosides (BEC) and is very effective for treating nonmelanoma skin cancers. Advantages of treatment of these lesions with Curaderm BEC5 compared with well established surgical interventions and other therapies have previously been reported as successful. The treatment time period with topical Curaderm BEC5 to completely eliminate skin cancers varies from days to months depending on size and type of skin tumours. Large non-melanoma skin cancers can be successfully treated with Curaderm BEC5 and it may take several months of treatment to eliminate these large tumours.

The incidences of non-melanoma skin cancers such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have increased more than 300 percent since 1992. For malignant melanoma, increased rates of over 500 percent have been reported from 1975 to 2008.

Limitations and costs of current treatments for skin cancers pose many shortfalls and many patients afflicted with these diseases do not seek proper treatment, resulting in increased morbidity and mortality. This report describes the successful treatments of vari- ous large BCCs by topical application of a cream formulation (Curaderm BEC5).

Combination therapy of intralesion and topical ap-plication of the same antineoplastic agents, Curaderm BEC5, result in rapid removal of a large BCC. Combination therapy of intralesion and topical treatment of BEC reduces skin cancer treatment period by about half when compared with topical treatment alone. The cosmetic end results of the treatments are excellent. This report also shows that intralesion injection of BEC alone, without CuradermBEC5 cream combination therapy, into a large melanoma of a horse results in the elimination of this potentially deadly skin cancer.

2. Materials and Methods

2.1. Patient Selection
One patient was a 68 year old farmer and was referred for consultation because he had multiple basal cell carcinomas of varying sizes. In particular, he also had a very large BCC on his back that often bled and was painful. This large BCC was a recurrence of a smaller BCC that was previously been removed by surgery and involvement a skin flap.

The patient who had these lesions for several years elected to treat various lesions with the cream formulation Curaderm BEC5. However, because of the size and pain associated with the large BCC, he requested to have this lesion treated by intralesion injection using the active ingredients solasodine glycosides (BEC) which are also present in the Curaderm BEC5 cream formulation. Patient’s informed consent for the treatment was obtained.

The sizes of the BCCs ranged from less than 2 cm in diameter (6 lesions) to approximately 3 cm × 3 cm × 0.5 cm (4 lesions) to 5 cm × 5 cm × 1.5 cm (1 lesion). Histological analyses of biopsies revealed that these lesions were BCCs.

A horse had an histologically diagnosed melanoma on the chest. This lesion was present for at least six months. The surface area of the lesion measured 5 cm × 4 cm and protruded approximately 1 cm. The owner of the horse was referred to our centre by his veterinarian and requested treatment with BEC for his horse’s melanoma.

2.2. Treatments Administered

2.2.1. BEC—Solasodine Rhamnosyl Glycosides
Glycoalkaloids (BEC) were extracted from the fruit of S. sodomaeum also known as S. linnaeanum (devil’s apple) and S. melongena (eggplant) essentially as described earlier. BEC is a mixture of solasodine glycosides consisting of the triglycosides solasonine (33%), solamargine (33%), and di-and monogly cosides (34%). All the glycosides contain the same aglycone, solasodine. Figure 1 shows the chemical structures of solasonine and solamargine and Figure 2 shows their mass spectra.

 

In the present studies the extract containing the mixture of these glycoalkaloids was investigated. Just prior to the current set of experiments BEC was analyzed by HPLC and it was shown to consist of 33% solasonine, 33% solamargine and 34% of di- and monoglycosides of solasodine.

2.2.2. CuradermBEC5 Topical Cream Formulation
The cream formulation CuradermBEC5 is available to patients in several countries. Curaderm BEC5 contains the glycoalkaloids BEC at 0.005% as a topical cream formulation. The cream is applied twice daily (when possible every 12 hours) under occlusive dressing (micropore paper tape) until the lesion is clinically regressed.

2.2.3. BEC in DMSO Solution for Intralesion Injection
A sterile solution of 10% BEC in dimethylsulfoxide, w/w, was used in this study.

The weight of the large BCC on the back of the human was approximately 50g. The doses injected intralesionally were approximately 100mg BEC per 1kg tumour weight. In the human subject, with the BCC tumour weight of approximately 50g, the dose was 50 microlitres of the 10% BEC solution and for the horse, with the melanoma tumour weight of 25g, the dose was 25 microlitres of the 10% BEC solution. The human and horse were injected intralesionally on 2 separate occasions. The second injection occurred approximately 48 hours after the first injection. Each injection was done intralesionally on multiple sites of the tumour including at the juncture of the lesions with the surrounding normal skin. No anaesthetic was used during the treatment regimes.

3. Results
The patient had several BCCs that were treated only with the topical cream formulation CuradermBEC5. The six BCC lesions which were less than 2 cm in diameter all regressed after 6 weeks with Curaderm BEC5 topical treatment (not shown).

Figure 3(a) shows a BCC before Curaderm topical treatment. The lesion’s size was approximately 3 cm × 4 cm and protruded 0.5cm from the skin’s surface. Figure 3(b) shows that the lesion was reduced considerably after six weeks of treatment. Figure 3(c) shows that the lesion was completely ablated 16 weeks after commencement of Curaderm BEC5 therapy.

Similarly, Figure 4 shows another BCC of approxi-mately 3 cm × 3 cm × 0.5 cm before (Figure 4(a)), six weeks during treatment (Figure 4(b)). After 16 weeks the lesion had clinically regressed (Figure 4(c)).

Figure 5(a) illustrates what appears to be three indi vidual BCCs. Closer clinical examination revealed that the three BCC lesions were interconnected. Six weeks of topical CuradermBEC5 therapy resulted in the erosion of the entire area (4 cm × 4 cm) including the spaces between the previously apparent distinctive lesions (Figure 5(b)). After 16 weeks there was no evidence of residual tumour (Figure 5(c)).

Figures 6(a) and (b) show a raised BCC of approxi mately 3 cm × 3 cm × 1 cm before Curaderm BEC5 treatment. Six weeks of treatment resulted in haemorrhagic necrosis of the tumour mass (Figure 6(c)) and 16 weeks after commencement of treatment, complete remission had occurred (Figure 6(d)).

Clinical evaluation indicated that the lesions of figures 3 to 6 were eliminated 14 weeks after topical Curaderm BEC5 treatments. The cosmetic end results, as shown at 16 weeks after commencement of treatments, were outstand-ing and there were no scar tissues at the sites of the treated lesions. During the first week of treatment, the patient experienced a stinging to mild burning sensation which lasted for approximately 20 minutes after topical application of Curaderm BEC5.

Figure 7(a) shows a large 5 cm × 5 cm BCC before combination treatment with intralesion injection followed by CuradermBEC5 topical treatment. Figure 7(b) illustrates that this lesion protruded 1.5 cm from the skin’s surface. Two days after the first injection of BEC in DMSO, but before the second injection, the lesion had already started to breakdown (Figure 7(c)). The odour of DMSO and necrosing tissue were noticeable. Two days after the second and final injection of BEC in DMSO, the necrosing le- sion had released itself from the skin Figure 7(d). The patient experienced some pain when BEC in DMSO was injected, especially at the site of the juncture of the lesion with the surrounding normal skin. The pain lasted for several minutes. After the bulk of the lesion was separated from the skin Figure 7(e), the patient followed up with Curaderm BEC5 topical application. Clinically this lesion was eliminated after 6 weeks of CuradermBEC5 topical treat-ment. Sixteen weeks after commencement of treatment, there was no evidence of residual tumour Figure 7(f). However, some scar tissue could be seen. The patient recol- lected that the scar tissue was due to a previous surgical procedure where a skin-flap was performed. However, after the previous surgical removal, the lesion reoccurred with rapid growth.

Figure 8 illustrates that intralesion injection of BEC solution alone, without additional topical CuradermBEC5 therapy, eliminates a large melanoma on a horse. In this case it can be seen clearly that there is a serumal exudate caused by the injection. This indicates that acute wound healing is in process despite that the cancer is being eli- minated during treatment. Thus, while the cancer cells are being killed in the presence of BEC, normal cells are replacing the killed cancer cells and normal cells are not killed by BEC therapy.

Curaderm on BCC on back

BCC on back

Melanoma on Horse treated with Curaderm

4. Discussion
SRGs which are BEC are a new class of antineoplastic chemotherapeutic agents. BEC is extracted from various Solanum plant materials and expresses its antineoplastic activities by highly ordered specificity and cancer cell destroying ability due to apoptosis and oncosis triggered by extrinsic and intrinsic apoptotic pathways.

It has also been reported that BEC or its individual component solamargine is far more effective than other established antineoplastics—taxol, cisplatin, gemcitabine, camphothecin, vinblastine, methotrexate, 5-fluorouracil, epirubicin and cyclophosphamide.

The observations in this current report that Curaderm BEC5 eliminates BCCs confirm many other published studies. The cosmetic end results after Curaderm BEC5 therapy are, as previously re-ported, excellent. This study confirms previous reports that topical Curaderm BEC5 therapy removes smaller BCCs within 6 weeks of treatment and for larger BCCs it takes approximately 14 weeks.

Previous studies have shown that intralesion administration of BEC in DMSO into very large skin tumours in animals resulted in removal of such lesions with excellent cosmetic outcomes. A report on a human subject has shown that 2 injections of BEC into a large SCC on the head resulted in the tumour collapsing and reduction in size. The large BCC injected with BEC in DMSO in this current study also exhibited rapid reduction in size. BEC intralesion administration resulted in the removal of the large extruding mass of the tumour two days after the second injection. To ensure complete removal of any possible remaining tumour cells after the intralesion injections the patient continued treatment with the Curaderm BEC5 cream. After 6 weeks of Curaderm BEC5 therapy the lesion was clinically ablated. Clinical observations indicate that the initial intralesion injections vastly reduced the subsequent time span treatment period with Curaderm BEC5 therapy. Because of the similar sizes of lesions treated by Curaderm BEC5 alone, and the lesion treated with intralesion and Curaderm BEC5, it appears that the combination therapy reduced the treatment period from 14 weeks to 6 weeks. Again, it was shown that the cos- metic result was excellent, although it cannot be excluded that the observed scar tissue was the same scar that was the result of the previous surgical procedure or if BEC may have contributed to its existence. Nevertheless, the cos-metic end result was very impressive.

Toxicity, lack of specificity and lack of efficacy with current antimitotic chemotherapeutic agents have led to more and more use of combination therapies when treat- ing cancer. Indeed, it has been shown that a combination of BEC with the widely used anticancer drug cisplatin has resulted in the effective treatment of cisplatin-resis- tant cancer cells, particularly lung cancer cells  and breast cancer cells.

Topical Curaderm BEC5 therapy successfully treats squa-mous cell carcinoma on the penis of humans. Intralesion administration of BEC into large multiple squa-mous cell carcinomas on the penis of a horse completely removes these tumours with excellent outcomes.

Successful treatment of Bowen’s disease (SCC) of the penis with CuradermBEC5 was recently reported. This tissue-sparing technique preserves functionality of the penis, is superior to other more-destructive treatment options for Bowen’s disease of the penis and confirms the efficacy of BEC and CuradermBEC5 when treating SCCs on the penis.

The main purpose of using combination therapy of BEC with other antimitotic drugs is because of the dif-ferent modes of actions of the individual antineoplastic agents.

The purpose for using BEC combination therapy as a liquid intralesion and topical Curaderm BEC5 cream, in this current communication, is not because there is a differ-ence in the mode of action of the combination therapy. In the current study it is the bioavailability of BEC to the cancer cells that is much enhanced when using the intralesion injections.

Massive haemorrhagic necrosis of the BCC tumour mass in the human patient occurred after intralesion in- jection. The large tumour separated entirely and dislocated itself from the skin. These observations are similar to a previous report where it was shown that a horse with mul- tiple large SCCs on its penis was injected intralesionally with BEC.

Intralesion injection of BEC in the large melanoma in a horse resulted in complete removal of the lesion. There were no apparent adverse effects. There was no recur- rence after more than 5 years follow-up. The results ob- tained in this study confirms previously reported studies where it was shown that intralesion therapy with BEC of large tumours of up to 0.5 kg were successfully removed. The specificity of BEC towards cancerous tissues was also shown in those studies. When normal tissue was injected with BEC no adverse effects occurred. Again, as with humans, the final cosmetic outcome after intralesion administration into very large tumours, was excellent.

The current observations are important, because it was previously shown that human melanoma cells in cell cul- ture studies are very susceptible to treatment with BEC [1-4]. Most recent studies have shown that intralesion ad- ministration of BEC may also have a very positive effect on immunological responses to tumours [24], how such observations relate to this current report is unknown. Fur- ther studies are warranted to establish whether intralesion injection of BEC into large BCCs, large nonmetastasized SCCs and non-metastasized melanoma (lentigo maligna or melanoma in situ) in man will result in the effective and rapid removal of these serious tumours.

Finally, the report confirms that smaller skin tumours can successfully be treated topically with CuradermBEC5 alone, resulting in excellent cosmetic outcomes. Studies of topical application of CuradermBEC5 have now been reported for malignant lesions on the face, trunk, limbs and penis. During treatment, patients develop areas of inflammation in and around the tumour, which then usually necrose, leading to ulceration and healing by re-epithelialization. The endpoint of the- rapy is achieved with regrowth of new skin at the treat- ment site. The cosmetic end results are most impressive. As little as two intralesion injections of low doses of BEC are required to eliminate a large melanoma, and, also re- duces treatment time by more than half when very large skin cancers are treated with CuradermBEC5. The cosmetic outcomes after CuradermBEC5 are almost unthinkable.