Phase II trial of ZD0473 as second-line therapy in mesothelioma

The platinum-containing compounds cisplatin and carboplatin represent the mainstay of chemotherapeutic treatment for a variety of solid tumors occurring in adults, especially testicular and ovarian cancers. These drugs confer their antitumor efficacy by binding to DNA, especially to guanine bases, either adjacent on the same DNA strand or across strands. Tumour resistance, either present at the onset of therapy or acquired during successive courses of therapy, represents the significant limiting factor to long-term patient survival. From numerous studies of cancer cell lines in vitro, it is apparent that tumor resistance to cisplatin may arise through two general mechanisms: one preventing sufficient platinum from binding to DNA (reduced membrane transport and cytoplasmic inactivation by thiol-containing species such as glutathione or metallothioneins); and a second whereby platinum-DNA damage does not result in cell death (enhanced DNA nucleotide excision repair, increased tolerance, loss of DNA mismatch repair, failure to undergo apoptotic programmed cell death). It remains largely unclear as to the relative importance of these mechanisms in the clinic or whether additional mechanisms also exist.

Overcoming Resistance to Platinum Therapy in Patients with Advanced Cancer

Purpose
ZD0473 is a cytotoxic platinum agent, which in preclinical studies has exhibited synergistic activity when combined with paclitaxel. The aim of this open-label phase I study was to determine the maximum tolerated dose (MTD), safety, and antitumour activity of ZD0473 followed by paclitaxel in patients with refractory solid malignancies.

A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies

ZD0473 combined with other chemotherapeutic agents for the treatment of solid malignancies.

AMD473 (ZD0473; cis-amminedichloro[2-methylpyridine]platinum [II]) is a new generation anticancer agent that, in preclinical studies, shows evidence of an extended spectrum of antitumor activity and overcomes platinum resistance mechanisms. Here we evaluate the activity of AMD473 (ZD0473) in a panel of 120 human tumor specimens using a soft agar cloning assay (human tumor colony-forming assay). When tumor cells were treated with 1.0, 4.0 or 16.0 microg/ml AMD473 (ZD0473) for 2 h, in vitro responses were observed in 18% (9/51), 33% (17/51) and 44% (19/43) of assessable specimens. Treatment of tumor cells with the same concentrations of AMD473 (ZD0473) for 24 h resulted in responses of 33% (16/48), 63% (30/48) and 85% (35/41). AMD473 (ZD0473) (16 microg/ml; 24 h) demonstrated activity towards 100% of the non-small cell lung (5/5) and ovarian (8/8) cancer specimens and 73% (8/11) of the breast cancer specimens treated. Low levels of cross-resistance to cisplatin cyclophosphamide, 5-flurouracil, etoposide and gemcitabine were observed. There was a positive relationship between AMD473 (ZD0473) concentration and effect, and a significant difference between response to 2- versus 24-h exposure to 4 or 16 microg/ml (p=0.003 and p=0.001, respectively). These responses demonstrate efficacy at pharmacologically relevant concentrations, suggesting AMD473 (ZD0473) deserves further evaluation.

AMD473 (ZD0473) exhibits marked in vitro anticancer activity in human tumor specimens taken directly from patients.

Activity of ZD0473 in small-cell lung cancer: an update in patients relapsing after one prior chemotherapy regimen

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Activity of ZD0473 in small-cell lung cancer: an update in patients relapsing after one prior chemotherapy regimen