o-(chloroacetylcarbamoyl)fumagillol and Carcinoma--Non-Small-Cell-Lung

Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.

Topics: Angiogenesis Inhibitors; Angiostatins; Carcinoma, Non-Small-Cell Lung; Collagen; Cyclohexanes; Endostatins; Humans; Lung Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Plasminogen; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sesquiterpenes; Survival Rate; Thalidomide

Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions.. Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity.. The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy.. The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cyclohexanes; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; O-(Chloroacetylcarbamoyl)fumagillol; Paclitaxel; Sesquiterpenes; Treatment Outcome

Cancer-related deaths are caused principally by recurrence and metastasis arising from residual disease, whose therapeutic responses has been suggested to be substantially different from primary tumors. However, experimental animal models designed for evaluating the therapeutic responses of residual disease are mostly lacking. To overcome this deficiency, we have developed a preclinical model that recapitulates the progression for advanced nonsmall cell lung cancer (NSCLC). An archived Lewis lung carcinoma mouse tumor, propagated only through serial in vivo transplantation and never adapted to cell culture, was stably labeled using lentivirus-encoded biomarkers, consistently expressed through an RNA polymerase II promoter. Labeled tumors were inoculated into syngeneic immunocompetent mice to ensure superior tumor-host interactions. Primary tumors were resected on reaching a predetermined size, followed by treatment in a setting akin to postsurgical first-line adjuvant chemotherapy and routine imaging to monitor the progression of pulmonary metastasis. We discovered that efficacious treatment, instead of reducing disease growth rates, significantly prolonged disease-free survival and overall survival. As in the clinic, cisplatin-based regimes were more effective in this model. However, the response of metastases to specific agents could not be predicted from, and often opposed, their effects on subcutaneous "primary" tumors, possibly due to their distinct growth kinetics and host interactions. We here introduce a clinically relevant model of residual metastatic disease that may more accurately predict the therapeutic response of recurrent, metastatic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Lewis Lung; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Cyclohexanes; Disease Models, Animal; Disease Progression; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm, Residual; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Survival Rate; Treatment Outcome

The combined effects of TNP-470, a promising antiangiogenic agent, and SN-38, a camptothecin derivative, were evaluated in four human cultured cell lines derived from non-small cell lung cancer (NSCLC). Cytotoxicity experiments were determined by using a tetrazolium salt (MTT) assay. The inhibitory effects of TNP-470 on cell proliferation were dose related and the 50% inhibitory concentrations on these cell lines were 47.3-139.8 microM. Evaluation of drug interactions with isobologram and the combination index values showed that sequential exposure to SN-38 followed by TNP-470 produced synergistic effects in the four cell lines tested. Our findings suggest that such an angiocytotoxic chemotherapy might be promising for the treatment of NSCLC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cell Division; Cyclohexanes; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Irinotecan; Lung Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured