zd-6126 and Head-and-Neck-Neoplasms

To examine the antivascular and antitumor activity of the vascular targeting agent ZD6126 in combination with radiation in lung and head-and-neck (H and N) cancer models. The overall hypothesis was that simultaneous targeting of tumor cells (radiation) and tumor vasculature (ZD6126) might enhance tumor cell killing.. A series of in vitro studies using human umbilical vein endothelial cells (HUVEC) and in vivo studies in athymic mice bearing human lung (H226) and H and N (squamous cell carcinoma [SCC]1, SCC6) tumor xenografts treated with ZD6126 and/or radiation were performed.. ZD6126 inhibited the capillary-like network formation in HUVEC. Treatment of HUVEC with ZD6126 resulted in cell cycle arrest in G2/M, with decrease of cells in S phase and proliferation inhibition in a dose-dependent manner. ZD6126 augmented the cell-killing effect of radiation and radiation-induced apoptosis in HUVEC. The combination of ZD6126 and radiation further decreased tumor vascularization in an in vivo Matrigel angiogenesis assay. In tumor xenografts, ZD6126 enhanced the antitumor activity of radiation, resulting in tumor growth delay.. These preclinical studies suggest that ZD6126 can augment the radiation response of proliferating endothelial H and N and lung cancer cells. These results complement recent reports suggesting the potential value of combining radiation with vascular targeting/antiangiogenic agents.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Caspases; Cell Line, Tumor; Cell Proliferation; Collagen; Combined Modality Therapy; Drug Combinations; Drug Screening Assays, Antitumor; Endothelial Cells; G2 Phase; Head and Neck Neoplasms; Humans; Laminin; Mice; Mice, Nude; Neovascularization, Pathologic; Organophosphorus Compounds; Proteoglycans; Random Allocation; S Phase; Umbilical Veins

Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.0336) in these tumour xenografts compared to Detroit 562- and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; Gefitinib; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Organophosphorus Compounds; Quinazolines; Sensitivity and Specificity; Treatment Outcome; Xenograft Model Antitumor Assays

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. Mice bearing the tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received a hypoxic cytotoxin, tirapazamine (TPZ) or TX-402, with or without a vascular targeting agent (VTA), ZD6126. Another group of mice given ZD6126 received a series of test doses of gamma-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors. After each treatment, the tumor cells were isolated and incubated with a cytokinesis blocker (cytochalasin-B), and the micronucleus (MN) frequency in cells without BrdU labeling [quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumor cells was determined from the tumors that were not pretreated with BrdU. Both hypoxic cytotoxins showed significantly greater toxicity toward SAS/mp53 and Q than SAS/neo and total tumor cells, respectively. The sensitivity to TX-402 was significantly higher than that to TPZ in both total and Q tumor cells of both tumors. The significant enhancive effect by ZD6126 combined with each hypoxic cytotoxin was similar irrespective of p53 status, and slightly greater for total than Q cells probably because of a more marked increase in the size of the HFs in total than Q cells on the use of ZD6126 in both tumors, resulting in a reduction of the difference in the sensitivity to the hypoxic cytotoxin between total and Q cells. In the treatment of conventional cancer therapy-resistant Q tumor cells or p53-mutated tumor cells, the use of hypoxic cytotoxin was very promising either alone or when VTA was co-administered. TX-402 might be more promising than TPZ, although further study of the toxicity to normal tissue is needed.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Combined Modality Therapy; Cyclic N-Oxides; Gamma Rays; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Micronucleus Tests; Mutation; Organophosphorus Compounds; Quinoxalines; Radiotherapy; Tirapazamine; Triazines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays