ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA.Poly(ADP-ribose) polymerase (PARP)-1is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m 2 /d temozolomide  5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m 2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m 2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m 2 AG014699 and 200 mg/m 2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.Multiple pathways contribute to the repair of damaged DNA (1). Defects in these pathways are a cause of cancer susceptibility (2, 3), but, when intact, their activity is a factor in tumor resistance to widely used DNA-damaging cancer treatments (e.g., cytotoxic drugs and ionizing radiation; ref. 4). Several novel agents are being developed which target DNA repair in an attempt to improve cancer treatment (5), including agents that may exploit tumor DNA repair defects (e.g., BRCA1 and BRCA2) by inducing ''synthetic lethality'' (6, 7).Base excision repair is a complex process that repairs DNA single-strand breaks caused by endogenous reactive species and anticancer agents (8). Poly(ADP-ribose) polymerase-1 (PARP) is a key enzyme in this pathway, binding to and being activated by the DNA break, effectively acting as a molecular nick sensor (9), and recruiting additional repair factors. Preclinical evidence has shown that inhibiting PARP potentiates cytotoxics, particularly alkylating agents and topoisomerase I inhibitors, and radiotherapy (10 -12). Several PARP

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O 6 -methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O 6 -methylguanine methyltransferase, which can eliminate the cytotoxic O 6 -methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.Intrinsic or acquired resistance to cytotoxic agents remains the greatest obstacle to the successful treatment of human cancer, and a variety of mechanisms of drug resistance have been identified in human tumors. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most rapidly growing and devastating cancers. Standard treatment consists of surgery followed by radiotherapy and chemotherapy with alkylating agents. Alkylating agents, including carmustine (bischloroethyl nitrosourea, or BCNU), lomustine (chloroethylnitrosourea), and temozolomide, readily cross the blood-brain barrier and have shown the most activity against malignant glioma. However, despite the ability of these agents to achieve therapeutic concentrations in the brain, malignant gliomas are often resistant to alkylating agents. Identifying and understanding the diverse mechanisms of chemoresistance operating in human tumors and developing effective strategies to overcome resistance is the focus of ongoing preclinical and clinical research.One important mechanism of resistance to alkylating agents is mediated by the DNA repair enzyme O 6 -methylguanine methyltransferase (MGMT; refs. 1, 2), which repairs O 6 -alkylguanine adducts. BCNU and chloroethylnitrosourea are bifunctional alkylating agents that form lethal double-strand cross-links (3). In contrast, the activity of methylating agents such as temozolomide and dacarbazine results in persistent O 6 -methylguanine adducts that initiate futile cycling of the DNA mismatch repair (MMR) pathway, which ultimately caus...