Cisplatin and DNA repair in cancer chemotherapy

Background

Great strides are currently being made in unraveling the molecular, cellular and genetic processes that give rise to cancer, however, this knowledge has yet to be translated into effective new cures for the disease. Chemotherapy continues to be a mainstay of treatment, with DNA-damaging agents being among the most effective classes of compounds in clinical use. Consequently, extensive investigations of compounds have been carries out both to understand their mechanisms of action and to overcome resistance, the single most common reason for discontinuation of a drug. The information presented in this study has implicated DNA repair as a key feature, making unexpected links between research on classical cytotoxic agents and the genetics of cancer.

Cisplatin

The inorganic compound cis-diamminedichloroplatinum(II), commonly referred to as cisplatin or cis-DDP, is one such anticancer drug that falls into the class of DNA-damaging agents. Cisplatin and its analogs are heavy metal complexes containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position.

Cisplatin has biochemical properties similar to that of bifunctional alkylating agents, producing interstrand, intrastrand and monofunctional adduct cross-linking in DNA.

Other platinum-DNA adducts including the monofunctional and the 1,3- and longer range intrastrand, interstrand and protein-DNA crosslinks; each of these adducts form a distinct structural element that interacts with DNA differently.

Cisplatin is apparently cell-cycle nonspecific. Following a single I.V. dose, Cisplatin concentrates in the liver, kidneys and small intestines in animals and humans. Cisplatin has poor penetration into the CNS. Plasma levels of radioactivity decay in a biphasic manner after an I.V. bolus dose of radioactive Cisplatin to patients. The initial plasma half-life is 25 to 49 minutes, and the postdistribution plasma half-life is 58 to 73 hours. During the postdistribution phase, greater than 90% of the radioactivity in the blood is protein bound. Cisplatin is excreted primarily in the urine. However, urinary excretion is incomplete with only 27% to 43% of the radioactivity being excreted within the first 5 days post-dose in humans beings. There are insufficient data to determine whether biliary or intestinal excretion occurs.

Cisplatin is indicated as palliative therapy to be employed against: Metastatic testicular tumors - Most effective

• Ovarian
• Head
• Neck
• Bladder
• Cervical
• Lung
• Other neoplasm's

There are two major limitations to Cisplatin therapy:

1. Toxic side effects.
2. Acquired resistance, especially for ovarian cancer.

Resistance to Cisplatin

The mechanisms by which cells develop resistance to cisplatin is an area of intense research because it is one of the major impediments to the clinical success of this drug. The invulnerability of cells to cisplatin cytoxicity has been attributed to several processes including:

1. The inhibition of drug uptake
2. An increase in the production of cellular thiols
   
   • methallothioneins
   • glutathione Both of which block the formation of DNA adducts
3. Enhanced replicative bypass of the cisplatin-DNA adducts
4. Changes in the concentration of regulatory proteins
5. A increase in the repair of cisplatin-DNA adducts.

There are two kinds of resistance to Cisplatin:

1. Acquired resistance: This type of resistance develops both in patients undergoing chemotherapy and in cell lines exposed to increasing concentrations of cisplatin until they have reached a high tolerance for the drug. In many cell lines, DNA repair has been implicated as a cause of resistance, but since the extent of repair did not correlate exactly with the degree of acquired resistance, other mechanisms, such as those mentioned above must have been operative.
2. Intrinsic resistance: This type of resistance is a phenomenon encountered in patient tumors that are naturally unaffected by platinum treatment. Some cell lines cultured from these patients were more proficient at removing cisplatin-DNA adducts than cell lines with normal cisplatin sensitivity. However, experiments using these cell lines did not examine the possibility that resistance in tumors may be due to mechanisms that are only manifest in vivo.

DNA repair and Cisplatin therapy

The increase in DNA repair that accompanies cisplatin resistance could be caused by enhanced expression of proteins involved in repair.

DNA polymerase beta

DNA polymerase beta is reported to be the only polymerase that will efficiently bypass a cisplatin 1,2-d(GpG) intrastrand crosslink, suggesting that higher expression levels of this protein will increase replicative bypass.

ERCC1

ERCC1 is one of the essential components of the mammalian Nucleotide Excision Repair (NER) pathway. When relative expression of the gene encoding for ERCC1 was monitored in tumor tissue from human ovarian cancer patients, the mRNA levels were significantly higher in tissue from patients who were clinically resistant to cisplatin therapy when compared with the tissue of patients who responded favorably to treatment.

Proliferating Cell Nuclear Antigen (PCNA)

Proliferating Cell Nuclear Antigen (PCNA) is another protein that is required for the NER pathway to function and this protein was also found to be overexpressed in cell lines that showed resistance to cisplatin exposure.

C-fos and C-myc

C-fos and C-myc are both proto-oncogenes that have been correlated with cisplatin resistance following drug exposure. Activating the transcription of these genes may lead to a cascade of gene expression that, in turn, stimulates the activity of proteins having a direct role in DNA repair.

p53

p53 is a tumor suppressor gene product that has been linked to the ability of DNA repair to confer cisplatin sensitivity. Disruption of the gene encoding for p53 in human breast cancer cells increased their sensitivity to cisplatin, possibly because of a decrease in DNA repair.

Conclusion

Cisplatin is a very successful anticancer agent and its success has led to the discovery of additional generations of platinum drugs. DNA repair plays a critical role in cellular resistance to cisplatin and, in turn, this DNA-crosslinking agent has aided in revealing the intricacies of the NER pathway. As additional details of the mechanisms of acquired and intrinsic cisplatin resistance emerge, the design of new platinum drugs should improve the overall response rates and long-term survival obtained for a broader range of tumors.

Cisplatin can be found under three trade named.

• Platinol
• Blenoxane
• Velban