Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
Purpose Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors. Methods Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed. Results Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1–4, 8–11, 15–18, and 22–25, and 100 mg/m2 paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7–28 weeks). Conclusions This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.
Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phosphorothioate-modified antisense oligonucleotides has antitumor efficacy in xenograft models of SCCHN. Because intratumoral delivery of therapeutic agents has limited clinical application, the present study was undertaken to examine the therapeutic mechanisms of systemically delivered phosphorothioate-modified EGFR antisense oligonucleotides alone, or in combination with docetaxel, in a SCCHN xenograft model. EGFR antisense oligonucleotides were administered at 5 mg/kg i.p. daily in athymic mice bearing 1483 human SCCHN xenografts alone or in combination with docetaxel at 2.5 mg/kg i.p. once a week for 4 weeks. Administration of EGFR antisense oligonucleotides in combination with docetaxel improved antitumor efficacy and resulted in lower expression levels of EGFR, fewer proliferating cells, and more apoptotic cells in the tumors compared with controls. Systemic administration of phosphorothioated EGFR antisense oligonucleotides for 30 days increased the retention of docetaxel in the tumor by approximately 4-fold compared with tumors treated with docetaxel alone or docetaxel and EGFR sense oligonucleotides (P Ͻ 0.05). Combination of EGFR antisense oligonucleotides with low doses of docetaxel has antitumor efficacy, and it may be an effective treatment strategy for SCCHN.Standard therapeutic regimens for squamous cell carcinoma of the head and neck (SCCHN) patients include surgery, radiation, and chemotherapy. Surgical extirpation often leads to functional impairment and the toxic effects of radiation and chemotherapy can be debilitating. Recent evidence suggests that combining standard therapy with agents that inhibit specific molecular targets may increase patient survival (Bonner et al., 2006). The epidermal growth factor receptor (EGFR) is overexpressed in 90% of SCCHN tumors. Activated EGFR triggers increased cell proliferation, angiogenesis, and metastasis, contributing to tumor progression and decreased survival and indicating that EGFR may serve as a therapeutic target for SCCHN. Various strategies targeting EGFR have demonstrated antitumor efficacy in preclinical models. Recently the Food and Drug Administration approved the use of the anti-EGFR antibody cetuximab as a monotherapy or in combination with radiotherapy for SCCHN patients. In addition to blocking EGFR activation, down-modulating EGFR protein levels via an antisense DNA approach has been reported to be an effective way of inhibiting EGFR-mediated growth. A direct comparison between EGFR antisense gene targeting and an EGFR tyrosine kinase-specific inhibitor or EGFR monoclonal antibodies demonstrated increased growth inhibition with antisense gene treatment compared with either of the other EGFR-targeting modalities (Grandis e...
2576 Background: STEALTH liposomal CKD-602 (S-CKD602), a camptothecin analogue, is eliminated by the reticuloendothelial system (RES), which consists of cells including monocytes. CKD-602 released from S-CKD602 is eliminated by the kidney. Therefore, we evaluated the PD relationship between monocyte and absolute neutrophil counts (ANC; as a control) in blood and S-CKD602 and non-liposomal CKD-602 (NL-CKD602) in patients (pts) with refractory solid tumors. We also evaluated the effect of age on these relationships. Methods: In a phase I study, S-CKD602 was administered IV x 1 q 3 wk at 0.1 to 2.5 mg/m2. In phase I and II studies, NL-CKD602 was administered IV qdx5d q 3 wk at 0.5 to 0.9 mg/m2/d and 0.5 mg/m2/d, respectively. The % decreases in ANC and monocytes at nadir were calculated. For S-CKD602, pharmacokinetic studies of encapsulated (E), released (R), and sum total (ST=E+R) CKD-602 in plasma and ST in urine were performed and measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated. Results: For S-CKD602 in all pts (n = 27), the % decrease in ANC and monocytes were 42 ± 30 % and 58 ± 34 %, respectively (P = 0.003). For S-CKD602 in pts < 60 years old (yo) (n = 12), the % decrease in ANC and monocytes were 43 ± 31% and 58 ± 26 %, respectively (P = 0.001). For S-CKD602 in pts = 60 yo (n = 15), the % decrease in ANC and monocytes were 41 ± 31% and 45 ± 36 %, respectively (P = 0.50). For NL-CKD602 (n = 42), % decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between % decrease in monocytes and released CKD-602 AUC in plasma in pts < 60 yo (R2 = 0.54) and = 60 yo (R2 = 0.49) was similar. For S-CKD602, the relationship between the % decrease in monocytes and the amount of CKD-602 recovered in the urine was stronger in pts < 60 yo (R2 = 0.82) compared with = 60 yo (R2 = 0.30). Conclusions: Monocytes are more sensitive to S-CKD602 compared with neutrophils and the increased sensitivity is related to the liposomal formulation and not CKD-602. These results suggest that monocytes engulf S-CKD602 which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in pts < 60 yo. [Table: see text]
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