Cisplatin ovarian cancer

Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl ] Med 2006 354 34-43. 

Neijt IP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carbo-platin in advanced ovarian cancer. J Clin Oncol 2000 18 3084-3092. 

Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer a gynecologic oncology group study. J Clin Oncol 2003 21 3194-3200. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

SH-SY5Y neuroblastoma, cisplatin-sensitive A2780 and cispla-tin-resistant A2780cis human ovarian cancer cells was observed, but upon irradiation 7 strongly reduced the viability of the cancer cells (Fig. 8). In the A2780 cell line, the complex was 80x more toxic than cisplatin under identical conditions, and ca. 15 x more effective against the cisplatin-resistant A2780cis cell line (33). The trans diazido-Pt(IV) complex therefore has remarkable cytotoxic properties. 

Two milestones in chemistry may be addressed to the geometric isomers of diamminedichloroplatinum(II). About 100 years ago Alfred Werner laid down the principles of modem coordination chemistry with the help of isomeric [PtCl2(NH3)2] [1]. About 70 years later Barnett Rosenberg and co-workers discovered that the cis isomer is antitumor active, whereas the trans isomer is not [2,3]. Today m-[PtCl2(NH3)2] (cisplatin) is routinely used as a drug, particularly effective against testicular and ovarian cancer [4],... 

Kikuchi, Y., Sasa, H., Kita, T., Hirata, J., Tode, T., and Nagata, I. (1991). Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects of cisplatin in vivo. Anticancer Drugs 2, 6S-67. 

Ma J, Maliepaard M, Kolker HJ, Verweij J, Schellens JHM (1998a) Abrogated energy-dependent uptake of cisplatin in a cisplatin-resistant subline of the human ovarian cancer cell line IGROV-1. Cancer Chemother Pharmacol 41 186-192... 

Arora S, Bisanz KM, Peralta LA et al (2010) RNAi screening of the kinome identifies modulators of cisplatin response in ovarian cancer cells. Gynecol Oncol 118 220-227... 

Brown R. Cisplatin resistance in ovarian cancer. In (Kelland LR, Farrell N, eds) Platinum-Based Drugs in Cancer Therapy 2000 Humana Press Inc. Totowa, NJ pp. 115-128. 

Reed FP, Yuspa SH, Zwelhng LA, Ozols RF, Poirier MC. Quantitation of cisplatin-DNA intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy. J Clin Invest 1986 77 545-550. 

Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer three-year results. J Natl Cancer Inst 2000 92(9) 699-708. 

Cisplatin (dx-Diamminedichloroplatinum) is a divalent water-soluble platinum containing complex. It reacts directly with DNA, resulting in both intra-and inter-strand cross-links. It also causes DNA breaks and it inhibits DNA replication and RNA transcription. A mechanism for the occurrence of resistance appears to be an increased of the levels of DNA-excision repair enzymes. Cisplatin is used in combination therapies with other anticancer drugs in the treatment of testicular and ovarian cancers and it has also shown high activity against cancers of the bladder, head, neck and endometrium. It is administered intravenously by rapid injection or by continuous infusion. It is for more that 90% bound to... 

A systematic review in the Cochrane database of forty-nine trials of chemotherapy for advanced ovarian cancer involving 8763 women concluded The available evidence, although not conclusive, suggests that platinum-based chemotherapy is better than non-platinum therapy. There is some evidence that combination therapy improves survival compared with platinum alone. No difference in effect has been shown between cisplatin and carboplatin (see Advanced Ovarian Cancer Trialists Group, 1999). 

McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al. Cyclophosphamide and cis-platin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl JMed 1996 334 1-6. 

Cisplatin (Platinol) is an inorganic coordination complex with a broad range of antitumor activity. It is especially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and 06 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferentially cross-linked. This platinating activity is analogous... 

G. Other applications Herceptin has been combined with cisplatin in the treatment of heavily pretreated metastatic breast cancer. Treatment of patients with ovarian cancer is under investigation. A recent study demonstrated that Herceptin increased the clinical benefits of first-line chemotherapy—doxorubicin (or epiru-bicin) and cyclophosphamide or pacli-taxel—in metastatic breast cancer that overexpressed HER2. 

Investigators found that human breast cancer cell lines with BRCAl mutations showed a twofold to fourfold increase in apoptosis after treatment with ionizing radiation, cisplatin, or doxorubicin, compared with cells free of mutations. They also found that BRCAl tumor cell lines were resistant to other agents, such as paclitaxel (Taxol) and docetaxel (Taxotere), treatments used commonly in ovarian cancer and advanced-stage breast cancers. 

Hence women with BRCAimutations who develop breast or ovarian cancer may not be good candidates for treatment with certain types of chemotherapy agents such as Taxol. Doxorubicin, cisplatin, or other newly discovered agents might be a better choice. In the future, genetic profiling may point the way to optimal treatment of cancer. 

It has been demonstrated that the human myeloid zinc finger (MZF1) (92) functions as a transcription repressor regulating ERCCl transcription in response to cisplatin-induced DNA damage. It was found that MZFl mRNA is constitutively expressed in human ovarian cancer cells. Quantitative PCR in the same cells showed that MZFl mRNA was decreased upon cisplatin exposure (93). Therefore, decreased expression of MZFl is a mechanism to be further investigated. 

Li Q, Gardner K, Zhang L et al. Cisplatin induction of ERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells. J Biol Chem 1998 273 23419-23425. 

Cisplatin Forms intrastrand and interstrand DNA cross-links binding to nuclear and cytoplasmic proteins Non-small cell and small cell lung cancer, breast cancer, bladder cancer, gastroesophageal cancer, head and neck cancer, ovarian cancer, germ cell cancer Nausea and vomiting Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve dysfunction... 

Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridanda-pani S, Anant S, Kuppusamy P. 2007. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther 6 178-184. 

Pietras, R. J., Fendly, B. M., Chazin, V. R., Pegram, M. D., Howell, S. B., and Slamon, D. J. 1994. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9 1829-1838. 

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