Combination therapy with anticancer drugs

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... 

Bryostatins are another class of compounds that bind to the Cl domain and result in acute activation of PKC. However, unlike phorbol esters, these marine natural products have antitumor effects. Bryostatins are currently in phase II clinical trials and show promise as anticancer drugs, particularly when combined with other adjuvant therapy. 

Paclitaxel is among the most active of all anticancer drugs, with significant efficacy against carcinomas of the breast, ovary, lung, head, and neck. It is combined with cisplatin in the therapy of ovarian and lung carcinomas and with doxorubicin in treating breast cancer. 

We have examined the effects of llavonoids and isoflavonoids on the P-gp-and MRP- mediated MDR mechanisms in both mouse lymphoma and human breast cancer cell lines. The interactions of the drug transporters P-gp or MRP with flavonoids or isoflavonoids might be worth their use as anticancer agents, such as a single administration or a combination cancer therapy with cytotoxic agents such as mitomycin C (MMC). Differences in the activities of the P-gp and the MRP-mediated efflux pump could be found in the presence of flavonoids and isoflavonoids. 

Although many other alkaloids have been isolated from C. roseus only vinblastine and vincristine have been developed for clinical use. The antiproliferative activity of the two compounds is related to their specific interaction with tubulin, thus preventing assembly of tubulin into microtubules and arresting cell division (59). However, despite this apparent identical mechanism of action and their clear chemical similarities, vinblastine and vincristine display very different clinical effects. Vinblastine, for example, is used to treat Hodgkin s disease and metastatic testicular tumors, whereas vincristine is used mainly in combination with other anticancer drugs for the treatment of acute lymphocyticleukemia in children. Toxicity profiles are also different, in that vinblastine causes bone-marrow depression, whereas peripheral neuropathy often proves to be dose-limiting in vincristine therapy. 

Teniposide is about 10 times more potent than etoposide in causing DNA damage in vitro and in vivo. In 21 of 733 children with acute lymphoblastic leukemia in remission, who received maintenance therapy with teniposide once or twice weekly in combination with other anticancer drugs, the risk of secondary acute myelogenous leukemia was about 12 times higher than in patients who had been treated with less intensive schedules (for example a short course of teniposide for induction chemotherapy) (149). 

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