Ovarian cancer drug resistant

Chen JY, Shen C, Yan Z, Brown DP, Wang M. A systems biology case study of ovarian cancer drug resistance. Comput Syst Bioinformatics Conf. 2006 389-398. 

Table 4. Cytotoxicity of Selected Antitumor Agents Against Ovarian and Drug-Resistant Ovarian Cancer Cell Lines (IC50 nM)a...

The common mechanisms of drug resistance in ovarian cancer include (1) alteration of drug inactivation by agents such as glutathione-S-transferase (GST), (2) enhanced DNA repair,... 

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. 

Caponigro F, Willemse P, Sorio R, Floquet A, van Belle S, Demol J, Tambaro R, Comandini A, Capriati A, Adank S, Wanders J. (2005) A phase II study of sabarubicin (MEN-10755) as second line therapy in patients with locally advanced or metastatic platinum/taxane resistant ovarian cancer. Invest New Drugs 23 85-89. 

Johnson SW, Ozols RF, Hamilton TC. Mechanisms of drug resistance in ovarian cancer. Cancer 1993 71 644-649. 

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. 

Eliopoulos AG, Kerr DJ, Herod J, et al. The control of apoptosis and drug resistance in ovarian cancer influence of p53 and Bcl-2. Oncogene 1995 11 1217-1228. 

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... 

More recently, a similar approach was used successfully to investigate farnesyl transferase inhibitor treatment of ovarian cancer (52,53) and in describing the protein molecular basis for drug-resistance development in pancreatic cancers (5,54). 

Thbulin-polymerizing chemotherapeutic agents, such as taxanes, have been shown to be one of the most effective drug classes in the treatment of ovarian cancer. The clinical success of paclitaxel has stimulated research into compounds with similar modes of activity in an effort to emulate its antineoplastic efficacy while minimizing its less desirable aspects, which include non-water solubility, difficult synthesis, and emerging resistance. 

Either the catalytic subunit or both subunits are overexpressed in several drug-resistant human cancer cells such as cisplatin-resistant ovarian cancer cells and melphalan-resistant prostate cancer cells, suggesting that elevated production of glutathione may induce drug-resistance mechanisms in these cancer cells (Figure... 

Cositecan (Karenitecin , BNP 1350) 54 (BioNumerik and ASKA Pharmaceutical) is currently being evaluated in a Phase III trial for the treatment of patients with advanced ovarian cancer who have become resistant to platinum and taxane drugs.110 Cositecan 54,111 114 which is also being evaluated against solid tumours in a Phase I trial, is an orally bioavailable, lipophilic 7-[2-(tri-methylsilyl)ethyl] derivative of camptothecin 55 which is less sensitive to both common and camptothecin-specific resistance mechanisms. Camptothecin 55 was first isolated in 1958 from Camptotheca acuminata (Nyssaceae) and its structure was reported in 1966.115 117 Camptothecin 55 was later shown to be a topoisomerase I inhibitor two camptothecin derivatives, topotecan and iri-notecan, are approved for chemotherapy use. 

Gemcitabine is a clinically active antineoplastic drug in platinum-refractory ovarian cancer. The efficacy and tolerability of the particular drug in combination with liposomal DXR were investigated in athymic mice bearing cisplatin-resistant human ovarian carcinoma [458]. 

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