Cisplatin resistant diseases

By using leukocytes from chemotherapy patients with squamous-cell carcinoma of the head and neck region, it was demonstrated that damage removal from DNA was related to cisplatin resistance [83], This type of study assumes the profile of adduct formation and repair to be the same in peripheral and tumor tissue. The hypothesis was supported by several early studies which employed either atomic absorption spectroscopy or immunochemical techniques to demonstrate a relationship between DNA adduct formation in blood cells and disease response [84-89]. Subsequent work revealed, however, that cisplatin-DNA adduct levels do not always correlate with survival [90] and can vary substantially between individuals [91]. 

The compounds were first tested against two panels of human tumour cell lines. The primary cell panel consisted of cells from tumours representative of different tissue types and with different chemosensitivities to cisplatin . Differential cytotoxicity, as opposed to non-selective toxicity, was used as an indicator of potential antitumour activity of test compounds . The second panel was disease-oriented and consisted of cell lines established from human ovarian tumours. This panel included two pairs of cisplatin-sensitive and cisplatin-resistant hnes, with defined mechanisms of resistance (CHl/CHl-R, A2780/A2780-R), and also two inherently resistant cell hnes (HX62 and SK-OV-3). This panel has been used to identify agents with the abihty to circumvent cisplatin resistance . ... 

Unfortunately, none of the seven randomized trials that have compared radiation therapy alone vs neoadjuvant cisplatin-containing chemotherapy plus radiation therapy demonstrated an improvement in overall or disease-free survival with combined-modality therapy (Table 2). Two studies actually demonstrated poorer survival with neoadjuvant chemotherapy. Souhami et al. (15) reported a significantly poorer survival rate with neoadjuvant chemotherapy in a small trial of patients with stage IIIB disease. This outcome was partly due to increased toxicity and poor compliance in patients who received chemotherapy. Another trial of neoadjuvant epirubicin and cisplatin was closed early when interim analysis revealed a significantly higher recurrence rate in the chemotherapy arm (16). These trials fail to provide any evidence that sequential cisplatin-containing chemotherapy and radiation therapy are of benefit. Possible explanations for the disappointing results include the effects of chemotoxicity, altered compliance, and possible accelerated repopulation of resistant clones after neoadjuvant chemotherapy. 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

Numerous clinical trials have demonstrated that carboplatin is substantially less toxic (especially in terms of nephrotoxicity and gastrointestinal effects see Table 1) than is cisplatin. Overview analyses of randomised studies comparing the activity of cisplatin versus that of carboplatin (mainly in ovarian and testicular cancers) have concluded that the two are broadly comparable in terms of response rates and disease-free intervals. However, it also appears that the two drugs are effective against the same population of tumours and thus share cross-resistance with one another. Notably, however, secondary responses to... 

Cancer has overtaken heart disease as the world s top killer by 2011, part of a trend that should be more than double global cancer cases and deaths by 2030. Cisplatin (cis diamminedichloroplatinum(II)) is one of the most effective anticancer drugs in the treatment of a variety of tumors and it has been clinically used widely. However, its limited usefulness in the development of resistance in tumor cells and the significant side effects have generated new areas of research, which mainly focused on searching for new metal-based... 

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