Cisplatin is supplied for clinical use as a lyophilised powder in vials that contain 10mg of the drug, a diuretic, usually mannitol, and salt, or as a 1 mg/mL aqueous solution. (Forrester et al 1993) Reconstitution of the powder is performed with sterile water to a concentration of 1 mg/mL, followed by further dilution with saline (usually 500 mL of 0.9% NaCl, USP) for intravenous (IV) administration over ½ to 2 h. Once reconstituted, the solution is kept at room temperature. Patients are hydrated regularly before, during and after cisplatin administration. A minimum of one to two litres of a dilute salt-containing liquid must be imbibed during pre- and post- administration. Typically, a total dose of 12.5 to 25g of mannitol with or without furosemide (20 mg), is given to increase urine flow, and an antiemetic to reduce the severity of the nausea caused by cisplatin. The specific dose of cisplatin, however, will vary from patient to patient, depending on a number of criteria, which include the reasons why this particular drug is being used, the patient's size, and whether or not other medicines are also being taken.
Recently, cisplatin has been shown to be more effective when given regionally to the site of the tumour. The most common method is intraperitoneal (IP) administration. Drug exposure in the peritoneal (abdominal/pelvic) cavity is about fifty times higher than intravenous (IV) administration. This type of therapy is most effective for ovarian cancers. Generally, the regimen for hydration and premedication is identical to that described earlier for intravenous therapy. A second method includes intraarterial delivery (as for hepatic tumours, melanoma, and glioblastoma), which undergoes similar precautions mentioned above.
The standard method of administering cisplatin is as a single slow intravenous injection or infusion every three to four weeks. Three hours after infusion, the drug is concentrated in the kidney, and at forty hours in the liver, intestine, and testes or ovaries as well. In the plasma most of it is bound to protein, where only about 10% of the remaining cisplatin is non-protein bound and active. Its clearance from the plasma is biphasic, with a primary half life of 25-49 minutes (distribution), and a secondary half life of 59-73 hours (elimination). The schedule appears to have little impact on activity as the total dose administered determines the level of antitumour activity. However, it has been reported that the actual time of day at which cisplatin is administered may affect the degree of toxicity. (Hardie et al, 1991) Bolus IV infusion of cisplatin (90 mg/m2) over a five minute interval at 08:00 appeared to be more nephrotoxic than the same dose given at 16:00.
Cisplatin is an effective drug against a wide variety of cancers. It has proved to be of benefit in the treatment of epidermoid carcinomas of the head and neck, refractory non-Hodgkins lymphomas, and cancers of the bladder, lung, breast, uterus, and cervix. However, the greatest impact of the drug has been towards the treatment of ovarian carcinomas and teratoma of the testes. Its effectiveness is mostly due to the inclusion of other antineoplastic agents into chemotherapy regimens. Such combination chemotherapy substantially improves the survival rate of patients with ovarian cancer, while for testicular cancer the outcome is very much better. Along with the agents vinblastine and bleomycin, cisplatin produces complete remission in 74% of patients with testicular cancer, and partial remission of the remaining 26%. A cancer is said to be in remission when all clinical evidence of the cancer has disappeared, ie, it is no longer detectable but not necessarily completely irradicated, as microscopic foci of cancer cells may remain. This high success rate is mostly due to synergistic effects, where multi-drug combination prevents the emergence of drug resistant strains of tumour cells. In addition, the use of a combination of agents is less toxic with respect to the total toxicity of each equivalent single agent.
One of the significant limitations towards the successful treatment of malignancies with cisplatin and other platinum-based drugs is the emergence of drug resistant tumour cells. Cellular resistance to these drugs is multifactorial and consists of complex mechanisms with a wide array of related and unrelated pathways. Some of the mechanisms identified...
These mechanisms, which may occur through the over-expression or inactivation of certain genes, have been identified primarily through the use of cell lines selected for cisplatin resistance in vitro. Such cells are obtained by exposure to sub-lethal concentrations, and biopsy specimens from patients' tumours.
Recent studies have shown ovarian carcinoma cells resistant to cisplatin, have considerably modified DNA for most of the twenty six chromosomes.
These were typically gene excision and insertion, which suggest that the acquired resistance to the drug may be associated with substantial genomic instability. The consequences of such wide genetic alteration would explain the occurance of the many mechanisms observed for cisplatin resistance. One important mechanism involves the inactivation of a cisplatin-dependent p53-accumulation pathway.
It was reported that
drug-resistance was not related to the amount of cross-links formed, but was partially due to this inactivation. Drug-resistant ovarian-cancer cells were shown to have a significant proportion of P53 (protein 53) in the cytoplasmic compartment and not in the nucleus. The consequence of this is reduced activation of DNA-damage repair mechanisms which would ultimately lead to apoptosis. (P53 is the primary regulatory protein that initiates repair mechanisms when it identifies altered DNA).
Studies of such mechanisms have identified a number of agents that may be administered to humans, which have reversed cisplatin resistance in vitro. For example,
Recent clinical trials have been focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial trials have shown that the addition of modulators of cisplatin can reverse resistance in patients previously failing therapy.
Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogues.
One tried and tested solution to combat drug-resistance is to prevent it from occuring in the first place. This typically involves the relatively new technique of high dose intensity chemotherapy.
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Put simply, the higher the dose of cisplatin, the more effective and beneficial it will be, thus reducing the chances of resistance from developing. However, cytotoxicity also increases with dosage, therefore, dose intensity is an important factor affecting survival.
The maximum potential drug effectiveness must be compromised to ensure that the patient remains relatively comfortable during treatment, while still having a good chance of successful chemotherapy and survival. To understand and appreciate why such compromise is necessary, one must be aware of the effects of cisplatin toxicity in the body and its degree of severity.
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