Cancer is a leading
cause of death worldwide1, second to cardiovascular disease. In the
UK, there are around 360,000 new cases of cancer every year2. This
may be attributed to aging population, chemical exposure and lifestyle.
Cancers is an
illness of the cells. Normal cells proliferate and after a certain number of
divisions go through programmed cell death, known as ‘apoptosis’. Cell growth
is tightly controlled by cell cycle checkpoints which are controlled by tumour
suppressor genes and proto-oncogenes. Carcinogenesis occurs when cells become
mutated, usually four times over, and proliferate uncontrollably giving rise to
a tumour. One common mutation is that of proto-oncogene ‘RAS’ being converted
to an oncogene3 resulting in uncontrolled cellular proliferation,
contributing to tumour growth. Tumors invade and metastasize to other tissues
and organs via blood and lymphatic vessels causing possible organ damage,
failure and unpleasant symptoms.
available for cancers are case and severity dependent, and aim to remove, kill or
prevent metastases of malignant cells. The treatments used to achieve these
outcomes are surgery, radiation and chemotherapeutic drugs. While these
treatments work, and cancer survival has doubled in the UK over the past 40
years1, mortality is still high and the need for new treatments is paramount.
drugs are ‘cytotoxic’ (toxic to cells) and target rapidly proliferating cells, which
is a primary characteristic of tumour cells. Within this report, 4 different
chemotherapeutic agents will be compared: paclitaxel, epidoxorubicin, tyrosine
kinase inhibitor (TKI) AG1478, and cisplatin. Each drug belongs to a different
class of drugs. Paclitaxel belongs to the taxane group and works by stabilising
microtubules and hence preventing depolymerisation4 such that the
spindles cannot shorten for use in mitosis. Epidoxorubicin is an anthracycline/
intercalating agent originating from the Streptomyces
and binds to DNA using its planar structure, causing interference with
topoisomerase II, resulting in inhibition of cell repair and apoptosis5.
Novel tyrosine kinase inhibitor (TKI), AG1478, binds, like gefitinib, to the epidermal
growth factor receptor6 and prevents auto-phosphorylation and decreases
growth signals being transduced to the nucleus6. Cisplatin, from the
platinate family, exerts its cytotoxic effects in a similar mechanism to the
alkylating agents. Platinates contain strongly nucleophilic groups which bind
the 7th nitrogen of guanine bases7, resulting in intrastrand
linkage in DNA and eventual apoptosis of DNA adducts7.
Cisplatin is licensed
in the UK for lung, cervical, head and neck cancers, both alone and in
combination8 and is currently being investigated as a neoadjuvant in
triple negative breast cancers as a single-agent and has proven in part
efficacious9, further research is required before this can be rolled
out in clinics. Despite its negative side effect profile, cisplatin has
remained a core chemotherapeutic agent in the clinics and is effective in
combination and as a single agent.
This report aims to
assess the outcomes of four anti-cancer drugs on cell viability with a focus on
cisplatin. Using IC50/pIC50 values derived from an MTT assay, an order of
potency should become apparent in hopes this can be used to enhance
pharmaceutical care in patients in a clinical setting.