BACTERIA TO GRAPPLE CANCER: BACTERIUM MEDIATED CANCER THERAPY (BMCT)

Cancer is characterized by uncontrolled and invasive growth of cells. These cells may spread to other parts of body and this is called metastasis. Cancer may be benign or malignant. The International Agency for Research on Cancer (IARC) estimates that 1 in every 5 people develop cancer during their lifetime. These new estimates suggest that more than 50 million people are living within 5 years of a past cancer diagnosis.

Conventional anticancer therapies consisting of surgical resection, radiotherapy, chemotherapy, are effective in management of many patients, but for about half of cancer sufferers these are ineffective. Resistance to conventional anticancer therapies has prompted the need for novel strategies.

The success of the alternative therapies depends on their cancer selectivity and reduced tissue toxicity. Despite being an  unconventional and contentious  therapy, the last two decades have seen a significant renaissance of bacterium mediated cancer therapy.

Scientists are harnessing a harmless soil bug to kill tumours by using it as a drug delivery vehicle. A bacterium found in the soil and harmful in its natural state has been converted through genetic methods into precise tumour destroyer. Researchers from USA’s John Hopkins Cancer Centre excised the toxin producing gene from the bacterium and the spores of. modified bacterium were introduced directly into the tumours and there was significant reduction in the tumour size or eradication without damaging healthy tissues.

The therapy uses Clostridium sporogenes – a bacterium that is widespread in the soil. Spores of the bacterium are injected into patients and only grow in solid tumours, where a specific bacterial enzyme is produced. An anti-cancer drug is injected separately into the patient in an inactive ‘pro-drug’ form. When the pro-drug reaches the site of the tumour, the bacterial enzyme activates the drug, allowing it to destroy only the cells in its vicinity – the tumour cells.

Bacterial anticancer therapy is an important weapon in the arsenal of fight against cancer. Strength of bacterial therapy depend in its specific targeting to the cancer cells. Different mechanisms responsible for anticancer activity include secretion of cytotoxic agent, immune engagement by the bacteria and engineered bacterial vectors for the expression and release of tumoricidal proteins.

Researchers at the University of Nottingham and the University of Maastricht have introduced a gene for a much-improved version of the enzyme into the C. sporogenes DNA. The improved enzyme can now be produced in far greater quantities in the tumour than previous versions, and is more efficient at converting the pro-drug into its active form.

Professor Nigel Minton, states that “Clostridia are an ancient group of bacteria that evolved on the planet before it had an oxygen-rich atmosphere and so they thrive in low oxygen conditions. When Clostridia spores are injected into a cancer patient, they will only grow in oxygen-depleted environments, i.e. the centre of solid tumours. This is a totally natural phenomenon, which requires no fundamental alterations and is exquisitely specific. We can exploit this specificity to kill tumour cells but leave healthy tissue unscathed,” he said.

The research will ultimately lead to a simple and safe procedure for curing a wide range of solid tumours. A successful outcome could lead to its adoption as a frontline therapy for treating solid tumours. If the approach is successfully combined with more traditional approaches this could increase our chance of winning the battle against cancerous tumours.

 Dona Basil, II^nd  Pharm D

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A SCARCE FORM OF NEOPLASIA

Hemophagocytic Lymphohistiocytosis (HLH) , also known as Hemophagocytic Syndrome, is an

Bone marrow smear of a patient with HLH

unconventional form of hematologic disorder seen more often in children than in adults. Unlike previously nowadays, HLH is prevalent among all age groups, including adults. This is a hyper inflammatory Syndrome which is caused by the uncontrolled proliferation of activated lymphocytes and macrophages, characterized by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines that makes it classified as one of the Cytokine Storm Syndrome. That is, it’s an anomalous feedback of the immune system.  Based on their etiologies, HLH can be classified broadly into two types - Primary and Secondary. Primary type expressly inherited form which is the Familial Hemophagocytic Lymphohistiocytosis and Secondary type that can be caused due to viral infections (Epstein-Barr virus), autoimmune diseases, Malignancy, Macrophage Activation Syndrome (MAS) etc.

The clinical presentations of HLH maybe difficult to find out as they are lot of symptoms that can mimic other conditions which bring up a way for many other differential diagnoses. However, the initial Signs and symptoms of HLH may include: Rash, Anaemia, Low Platelets and White Blood Cells, Enlarged Liver, Spleen and Lymph Nodes, Diligent Fever, Seizures, Liver Failure, Hepatitis, Jaundice etc.

Familial HLH, which is the Primary HLH maybe acquired from parents to children, but the Acquired HLH can be caused by,

• Viral infections, mainly Epstein-Barr virus
• Autoimmune diseases
• Bacterial or Fungal Infections
• Cancers, such as T-cell lymphoma

There are chances of being conditioned with X-linked lymphoproliferative disease (XLP), if one has an acquired HLH spawned by a virus.

The pathophysiology of the condition is due to an abnormally activated immune system can result in multiple organ damage and severe adverse events. NK cell cytotoxicity is centric in the development of HLH. Familial HLH presents with granule related cytotoxicity. An inability to properly recruit immune cells to the antigen site causes the cytokine storm. With an impending immune system, the release of excessive cytokines threatens the organs with a paramount cytokine infiltration. The clinical presentation of HLH can be attributed to such mechanisms operating behind it. Fever is primarily caused due to IL-6, TNF-alpha and IL-1. TNF-alpha also has other important role where in, it inhibits lipoprotein lipase and stimulates the synthesis of TG. TNF-alpha in conjunction with TNF-gamma promotes cytopenia with an attenuation in haematopoiesis. These pathways culminate in HLH. Ferritin and Plasminogen activator  which is secreted by activated macrophages may lead to hyperfibrinolysis.

The diagnosis for HLH is instituted through blood tests which include blood cell counts, liver function, markers of immune system activation such as ferritin and soluble IL-2 receptor levels. A bone marrow aspirate and biopsy may be performed to look for microscopic evidence of hemophagocytosis. A lumbar puncture may be performed to collect cerebrospinal fluid and to make sure the HLH is not affecting the brain. X-rays, CT scans, ultrasounds or MRIs may be performed.   

The therapy of the ailment maybe approached by:

·        Chemotherapy (cancer drugs)

·   Suppress the severe inflammation: Steroids- Dexamethasone; Cyclosporine A; Intrathecate Methotrexate, Hydrocortisone (patient with persistent active CNS disease)

·        Kill the over stimulated Antigen Presenting Cells: Etoposide (VP-16)

·        Treat the triggering agent: Antibiotic drugs, Antiviral drugs

·        Supportive Therapy: Prophylactic Cortimoxazole, Oral anti-mycoctic, Gasoprotection.

HLH is an uncommon but likely underdiagnosed disease. The mortality is uniformly high, and a timely diagnosis is imperative. Infections are common triggers in both genetic and acquired HLH. If not treated properly both the type may or may not lead to terminal multiple organ failure.

The disease had shown gender equivalence and estimation of universal generality of one in a count of 50,000. The genetic form is most likely to be present in the paediatric population and with some exceptional in adult population.

Angelin Jaimon Augustine , II Pharm - D