soblidotin and Lung-Neoplasms

The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1,027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3-4 weeks.. Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS) or=20 and <75 years. The patients were administered TZT-1,027 in escalating doses from 0.5 to 5.6 mg/m(2). Pharmacokinetic samples were collected during each treatment course.. Forty-nine patients were enrolled. Three patients had DLTs, including neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The common toxicities included constipation, anorexia, alopecia, nausea, leukopenia, and neutropenia. One complete response and three partial responses were observed. The pharmacokinetic parameters (AUC and C (max)) of TZT-1,027 tended to increase linearly with dose.. DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m(2). The recommended phase II study dose of TZT-1027 is 4.8 mg/m(2) administered every 3-4 weeks.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Female; Half-Life; Hematologic Diseases; Humans; Injections, Intravenous; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Oligopeptides; Treatment Outcome

: TZT-1027, a derivative of dolastatin-10, has a wide spectrum of in vitro activity against cancer cell lines. We conducted a phase 2 trial of TZT-1027 in patients with previously treated non-small cell lung cancer (NSCLC).. Patients with stage IV or recurrent NSCLC who had received one prior platinum-based chemotherapy regimen were eligible. Patients received 2.4mg/m(2) of TZT-1027 on days 1 and 8 of a 21-day cycle. The primary endpoint was response rate as measured by RECIST.. Thirty-two patients were enrolled (16 women, 16 men). The most common grade 3/4 adverse effects were leukopenia and neutropenia. Four patients died within 30 days of receiving TZT-1027, three from progressive disease and one with pneumonia and neutropenia. No objective response was observed (0% observed rate, 95% confidence interval 0-11%). The median time to progression was 1.5 months. The median overall survival was 8.5 months.. This phase 2 trial showed that TZT-1027 administered on days 1 and 8 of a 21-day cycle had no anticancer activity. Further development of TZT-1027 in patients with previously treated NSCLC is not warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oligopeptides; Survival Rate; Treatment Outcome

TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to gamma-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Cycle; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Mice, Nude; Microtubules; Models, Biological; Oligopeptides; Radiation-Sensitizing Agents; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.

Topics: Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cell Survival; Docetaxel; Erythrocytes; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia P388; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Neovascularization, Pathologic; Oligopeptides; Skin; Stilbenes; Taxoids; Transfection; Vascular Endothelial Growth Factor A; Vincristine

It has been revealed that chemotherapy using DNA-damaging agents and radiotherapy were influenced by the p53 status of tumors; however, p53 status did not influence chemotherapy using antimicrotubule agents. To elucidate whether a novel antimicrotubule agent, TZT-1027, is influenced by the p53 status of tumors, the authors investigated the sensitivities of specimens obtained from patients with nonsmall cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC) to various anticancer agents, including TZT-1027, and the status of the p53 gene in those specimens.. Twenty-nine NSCLC specimens and 22 RCC specimens were analyzed for their sensitivity to various anticancer agents and their p53 status. Sensitivities of the specimens to nine anticancer agents were determined by flow cytometric analysis. To determine p53 status, polymerase chain reaction amplification with primers for exons 5--9 was conducted, and the products were subjected to single-strand conformation polymorphism analysis.. In the NSCLC specimens, anticancer agents, including TZT-1027, showed strong antitumor activity against 50--75% of specimens with the wild type p53 gene. TZT-1027 showed strong antitumor activity against 40% of specimens with the mutant type p53 gene, whereas DNA-damaging agents showed such activity only in 16--28% of specimens. In RCC specimens, TZT-1027 showed potent antitumor activity in 29% of specimens with the wild type gene, and DNA-damaging agents showed such activity in 6--18% of specimens. TZT-1027 showed strong antitumor activity in 40% of specimens with the mutant type p53 gene, whereas DNA-damaging agents showed such activity only in 0--20% of specimens.. We found evidence to suggest that TZT-1027 was influenced less by the p53 status of specimens than DNA-damaging agents. Therefore, TZT-1027 is expected to show similar antitumor activity against tumors with a loss of p53 function as well as those with normal function of p53 in clinical fields.

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; DNA Damage; Female; Genes, p53; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Oligopeptides; Polymerase Chain Reaction; Tumor Cells, Cultured

Clinical use of TZT-1027, a microtubule-interfering agent that inhibits the polymerization of tubulin, is expected because of its potent effects on solid tumors. TZT-1027 is thought to act directly on cellular microtubules, and arrest cell mitosis, however, the molecular mechanisms of the microtubule damage by TZT-1027 have not been fully identified. To investigate the possible novel mechanisms of action of TZT-1027, we used the cDNA macroarray technique to examine its effect on the expression of hundreds of tightly transcriptionally controlled genes. We used two cell lines, one was human non-small cell lung carcinoma PC-14 cells as a model for cancer cells, and the other was human astrocytes as a model for normal neuronal cells, because the dose-limiting-factor of microtubule-interfering agents is mainly peripheral neurotoxicity. mRNAs prepared from the PC-14 and astrocyte cell lines treated with TZT-1027 were compared with 588 genes spotted onto the filter, and which gene groups TZT-1027 modulated between the two cell lines was investigated. TZT-1027 exposure modulated expression of a variety of genes including the genes encoding cell-cycle and growth regulators, receptors, angiogenesis and invasion regulators, rho family small GTPases and their regulators and growth factors and cytokines. However, the way of gene regulation by TZT-1027 exposure was different between PC-14 cells and astrocytes. Genes up-regulated in both PC-14 cells and astrocytes were those for RAR-epsilon, TNFR 1 and 2 and so on. Specifically altered genes in PC-14 cells, such as the genes coding for cytokeratin 8, XPG, fau and the genes regulated only in PC-14 cells may be involved in the antitumor activity of TZT-1027. On the other hand, growth factor receptor precursors was upregulated specifically in astrocytes by TZT-1027 and this gene regulation only in astrocytes may be candidates related with neurotoxicity.

Topics: Antineoplastic Agents; Astrocytes; Carcinoma, Non-Small-Cell Lung; Cells, Cultured; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Microtubules; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Oligopeptides; Up-Regulation

TZT-1027 was evaluated for its antitumor effects in sixteen human tumors xenografted in nude mice from gastric (H-81, H-106, H-30, H-154), breast (H-31, H-62), colon (H-110, H-143), lung (LC-376, H-74, Mqnu-1, LC-351), liver (H-181), renal cell (H-12) and ovarian (H-OC-3, SOC-4) cancer lines. In the latter three and lung (Mqnu-1, LC-351) cancers the results were compared with those obtained with CPT-11, VCR, CDDP, ADM. TZT-1027 showed effective antitumor activity (IR > or = 58%) against fifteen of the tumor lines, all but LC-351, and showed markedly effective activity (IR > or = 80%) against twelve tumor lines, including drug-resistant colon (H-110), lung (H-74) and ovarian (SOC-4) cancer lines. The complete regression was shown in five H-OC-3 tumor-bearing mice out of seven. Moreover, TZT-1027 was shown to be more potent in three cancer models (Mqnu-1, H-81, SOC-4) than CPT-11, and to have markedly effective antitumor activity in two cancers (H-12, H-OC-3) in which VCR was ineffective and in ovarian cancer (SOC-4) in which CPT-11, CDDP and ADM were ineffective. The administration of TZT-1027 induced fewer side effects; transient reduction of body weight was observed in four lines out of sixteen tested. These results suggest that TZT-1027 is an excellent candidate for clinical trials for the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Body Weight; Breast Neoplasms; Colonic Neoplasms; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Oligopeptides; Stomach Neoplasms

Dolastatin 10, a pentapeptide isolated from the marine mollusk Dolabella auricularia, has antitumor activity. TZT-1027, a dolastatin 10 derivative, is a newly synthesized antitumor compound. We evaluated its antitumor activity against a variety of transplantable tumors in mice. Intermittent injections of TZT-1027 were more effective than single or repeated injections in mice with P388 leukemia and B16 melanoma. Consequently, TZT-1027 shows schedule dependency. TZT-1027 was effective against P388 leukemia not only when administered i.p., but also when given i.v. However, although TZT-1027 given i.v. was active against murine solid tumors, TZT-1027 administered i.p. was ineffective against all the tumors tested with the exception of colon 26 adenocarcinoma. The i.v. injection of TZT-1027 at a dose of 2.0 mg/kg remarkably inhibited the growth of three murine solid tumors; colon 26 adenocarcinoma, B16 melanoma and M5076 sarcoma, with T/C values of less than 6%. The antitumor activities of TZT-1027 against these tumors were superior or comparable to those of the reference agents; dolastatin 10, cisplatin, vincristine, 5-fluorouracil (5-FU) and E7010. In experiments with drug-resistant P388 leukemia, TZT-1027 showed good activity against cisplatin-resistant P388 and moderate activity against vincristine- and 5-fluorouracil-resistant P388, but no activity against adriamycin-resistant P388. TZT-1027 was also effective against human xenografts, that is, tumor regression was observed in mice bearing MX-1 breast and LX-1 lung carcinomas. TZT-1027 at 10 microM almost completely inhibited the assembly of porcine brain microtubules. Therefore, its mechanism of antitumor action seems to be, at least in part, ascribable to the inhibition of microtubule assembly. Because of its good preclinical activity, TZT-1027 has been entered into phase I clinical trials.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cisplatin; Crosses, Genetic; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Humans; Leukemia P388; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Nude; Mollusca; Neoplasms, Experimental; Oligopeptides; Transplantation, Heterologous