Question 1

Question 1:
Colorectal carcinoma
It affects the rectum and the colon and occurs as a result of multiple genetic alterations accumulation. Interplay between environmental factors are genetic alterations provide an environment for colon cancer to be initiated. Sporadic colon cancer is due to accumulation of changes in tumor suppressor genes, and mismatch of DNA repair genes. Small number of these cancers are caused by inherited gene mutations. These include:
Familial adenomatous polyposis
Attenuated which is as a result of APC gene mutation. Normal growth and function of cell is altered with. Overgrowth causes polyps in the colon as well as extraintestinal manifestation, e.g. congenital hypertrophy. APC interacts with beta catenin which is an intracellular protein. Mutation of APC causes stabilization of catenin and translocation into the nucleus to interact with transcriptional factors to transactivate MYC and cyclins.

Catenin is a critical controller of cell growth.

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Almost all of the inherited APC mutations are frameshifting or nonsense changes and somatic changes rarely inactivate the gene fully.

Individuals suffering from inherited FAP remain healthy until when one cell suffers a second mutation.
Autosomal recessive resulting from MUTYH gene which prevents correction of errors during coping of DNA during cell division. This increases the chances of cell overgrowth and hence polyps.

FAP may become evasive carcinoma when they are left in place one or more of the polyps is likely certain to evolve.

Lynch syndrome
It is a non-polyposis cancer syndrome which results when genes which help in the repair of DNA which is damaged are mutated. It’s autosomal dominant and the genes: MLH1, MSH2 MSH6, PMS2 or EPCAM are mutated and hence proper DNA replication is disrupted and one of the manifestations include: microsatellite instability. Accumulated mutation leads to abnormal cell growth.

Peutz-Jeghers syndrome
Results from the mutation of the gene STK11 or LKB1, a tumor suppressor gene hence uncontrolled cell division.

MYH-associated polyposis (MAP)
It is an autosomal recessive gene caused by an alteration in the gene MYH.

Most of the colorectal carcinomas are acquired throughout life rather than inherited. 1st mutation occurs in the APC gene mutation. Other genes are then involved in the mutation, others of which are yet to be known.

Sporadic colon cancers involve inactivation of TP53 which is a tumor suppressor gene and SMAD4 gene on chromosome 18q.

Disease presentation
Most types start as polyps which are growths in the colon or rectum. These polyps are benign of which over the years some may progress into being malignant and cancerous. There are two main type of polyps:
Adenomas which are pre-cancerous because the they can either progress into cancer or not.

Hyperplastic and inflammatory polyps which generally are mostly seen and are pre-cancerous.

For a polyp to progress it has to grow into the walls of the rectum and the colon and grows outwards from the inner most layer of the colon.

This cancer has a range of stages from 0 to IV. 0 being the early stage and IV the late stage.

Disease progression
Sporadic colon cancers arise from the differentiation of normal mucosa to adenomatous polyps, precancerous. Only about 1/10 of the polyps become cancer in a duration of 5 to 10 years. Progression is favored by size and histology of polyps.

Adenomas might evolve through early, intermediate and late stages to become carcinomas and metastasize.

The principal observations include:
Early detectable lesions which have aberrant crypt foci and fail to express APC.

Early stage adenomas which show a global hypomethylation of CpG in a DNA strand.

Early adenomas’ KRAS oncogene mutates to evolve to intermediate adenomas.

Loss of heterozygosity on 18q by late adenomas and carcinomas.

Progression of colorectal carcinoma is a multistage which involves inhibition of the tumor suppressor genes and stimulation of oncogenes. Defects in the tumor suppressor gene is caused by loss of chromosomes 5q, 17p and 18q. development of the colorectal cancer occurs when cells in the colon and the rectum divide while uncoordinated.

Most of these cancers start as pre-cancerous, adenomas, then become cancerous and large when they spread and start showing symptoms.

According to gatekeeper hypothesis, sporadic cancers need 2 simultaneous mutation in the gatekeeper which leads to a permanent imbalance between cell death and cell replication. Effects of the mutation of the other genes is not long term is the gatekeeper is normally functioning.

Therapy
Radiotherapy uses radiation to destroy cancer cells which prevents recurrence of secondary implants near originally occurring primary tumor. Radiation is used to shrink the tumor for easier removal during surgery.

Chemotherapy is used together with radiotherapy to prevent colostomy or recurrence of the cancer.

Surgical resection which involves removal of tumor and surrounding healthy colon and rectal tissues.

To guide therapy with monoclonal antibody drugs such as panitumumab and cetuximab that target EGFR, KRAS which is a wild type of cancer that responds to these drugs is routinely mutationally analyzed.
Genetic therapy can now be used in cancer trials by using approaches which include:
Restoration of protective proteins, tumor suppressor gene.

Using a retroviral vector to inactivate oncogene expression.

Gene delivery to malignant cells to make them drug sensitive.

Making host cells resistant to drugs especially those used in chemotherapy and protein delivery to host cells for protection.

Making malignant cells more visible to immune systems.

Question 2:
Role and Application of genetic therapeutics in pharmacy
Gene Therapy is the transfer of DNA material to dysfunctional cells to correct a deficiency in the genetics of a patient.

Gene therapeutics can be used to target ovarian cancer where vectors are maintained within a closed cavity. Completely modified vector trials include multidrug resistant gene, liposome, retroviral and adenoviral.

Clinical gene therapy has been focused on the stem cells which are supposed to evolve into immune cells in order to make their mature forms resistant to HIV and hence aims to prevent HIV multiplication and spread to healthy cells. Several researches such as soluble forms of CD4, a cellular receptor of HIV to enter lymphocytes, dominant negative mutations which block HIV-directed proteins and RNA decoys are being investigated.

Vascular gene transfer provides prospective for new therapy for various cardiovascular disorders for example the use of therapeutically overexpression blood vessel endothelial growth factors and fibroblast GF including nitric oxide synthase among others to increase blood flow and vascular growth.

Cystic fibrosis is caused by a mutation in CFTR gene which leads to a malfunction of chloride and water transport outside the cell. Effective genetic therapeutics were found for this non-curable disorder when cultured in vitro in human cells and mice. copies of the CFTR gene in the genome of an adeno-associated virus, were used as a vector method of delivering the genetic correction to cells in the intestine because the virus only causes a slight immune response.

Most children with late infantile form of Batten disease are deficient of TPP1 gene and hence a research was don on dogs which also lacked TPP1 gene by delivering a corrective gene into dog’s specialized tissue using AAV and the specialized tissues started secreting TPP1 and with time clinical improvement were observed in the dog.

Parkinson’s disease which is a neurological disorder caused by deficiency of dopamine has been corrected by a trial on delivery of genes that code for 3 enzymes necessary for dopamine synthesis via the lentivirus vector delivered by ProSavin.

SCID-ADA which is a common type of severe combined immunodeficiency and trials have been used by manipulating retroviral vectors to deliver ADA genes.

Trials on malarial vaccine use adenovirus to deliver malarial antigen and tuberculosis vaccine studies use a combinant MVA virus to deliver tuberculosis antigen.

A clinical trial on leber congenital amaurosis improved patient’s vision slightly when Adeno Associated virus was used to deliver RPE65 to the retina of the eye which is usually deficient in such conditions.

Type I diabetes has successfully been treated by using adeno associated virus to deliver Pdx1 and MafA gene to the pancreas which induced conversion of alpha cells to beta cells.

References
Retrieved from https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(17)30472-1#secsectitle0010 on 20/11/2018
Retrieved from https://www.pharmaceutical-journal.com/files/rps-pjonline/pdf/cp200906_gene_applications-270.pdf on 20/11/2018