Background

The estimates of 2017 for bladder cancer by the American Cancer Society in the United States indicate that:

• New cases of bladder cancer are around 79,030; where around 18,540 is in women and 60,490 in men.
• Deaths resulting from bladder cancer are around 16,870; where around 4,630 is in women and 12,240 in men.

Recent years have seen a slight decrease in rates of deaths and new bladder cancers in women. For men, the death rates have remained stable, but the incidence rates are decreasing.

In the United States, bladder cancer contributes around 5% of all the new cancer cases being reported. In men, it has come out to be the fourth most common form of cancer though it is not very prevalent in women.

This cancer is attributed to the excessive growth of cells in the urinary bladder. The more this cancer cells develop, they have the ability of forming a tumor and usually spread to other body parts. The bladder is found in the pelvis where it is a hollow organ containing flexible, muscular walls. This is the organ that reserves urine before it is passed out. Ureters are the tubes responsible for carrying urine from the kidneys to the bladder. Urine passes out through the urethra when the muscles in the bladder contract.

The walls contained in the bladder tend to have a number of layers that are made up of cells of varying types. Most bladder cancers have been found to initiate from the bladder’s innermost lining normally regarded as the transitional epithelium or urothelium. The cancer becomes more severe and difficult to treat as it grows into other layers of the wall.

The cancer has the ability to grow outside the bladder and other nearby structures with time. The ability to spread to other body parts including the lymph nodes is also prevalent.

Bladder cancer is usually very expensive to treat due to its relapsing nature. Transitional cell carcinoma (TCC) is the most common bladder cancer. TCC constitutes 90% of all the bladder cancers and is derived from the urothelium (Bischoff & Clark, 2009). Metastatic or advanced bladder cancer can be treated through Cisplatin-based combination therapy (Cohen et al., 2006, Kaufman, 2006). Despite this being standard therapy treatment, the outcome of patients battling metastatic cancer has proven to be poor since the tumors become Cisplatin therapy resistant. This situation has been more troublesome since the factors that influence bladder cancer response to drugs and how the cancer resists Cisplatin are yet to be fully established.

Cisplatin

Cisplatin is being used as a chemotherapeutic agent when dealing with different types of tumors. The DNA is the primary cellular target even though it has the ability to react with protein and RNA too. Cisplatin has the ability of reacting with N7 atoms of purine bases in DNA once it has entered a cell and undergone activation through replacement of its two chloride ligands combined with water molecules to form a wide range of adducts that include monofunctional  adducts( this is where Cisplatin is bound to a single purine base), and inter- or intra-strand crosslinks  (this is where one Cisplatin binds to the N7 atom comprising two purine bases on one strand or opposing strands correspondingly).

DNA Repair System

In many cancer types, resistance to Cisplatin has been shown to be contributed by increased ability of detecting, manipulating and repairing damaged DNA. The nucleotide excision repair pathway (NER) that tends to deal with bulky adducts in DNA primarily is initiated when any adduct responsible for DNA helix distortion is detected. Cisplatin adducts have the ability of recruiting and activating NER proteins since they can distort the DNA. Cisplatin has remained to be a successful drug for treating testicular tumors due to its ability to express the proteins required for NER in low levels.

There are several steps contained in the NER pathway. Upon the detection of bulky adducts in DNA, a patch consisting approximately 30 bases is expunged by two distinct complexes (one 5’ to the damage and one 3’ to the damage). A polymerase then fills the gap using the undamaged strand as a template thereby, religating the DNA backbone by DNA ligase IV. The complex made of the XPF protein and excision repair cross-complementing group 1 protein (ERCC1) is frequently linked to Cisplatin resistance for many tumor types compared with other proteins involved in NER. ERCC1-XPF has been regarded to be responsible for the cutting of DNA backbone in the region 5’in the NER pathway. However, it also plays an imperative role in regulating sensitivity to Cisplatin adducts and the resolution of interstrand crosslinks.

There have been studies conducted in recent times that show an epigenetic mechanism for XPC downregulation in bladder cancer coupled with histone deacetylase 4 (HAD4) involved in XPC silencing in addition to increased HDA4 in bladder tumors that correlate with increased cancer sensitivity.

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