ac-7700 and Lung-Neoplasms

The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models.. In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated.. Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2).. A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level.. ClinicalTrials.gov number, NCT01095302.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma, Non-Small-Cell Lung; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Serine; Taxoids; Treatment Outcome

DISRUPT evaluated whether adding the vascular-disrupting agent ombrabulin to a taxane-platinum doublet in the first-line setting improved progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC).. Patients were randomised to ombrabulin 35 mg/m(2) or placebo followed by a taxane-platinum regimen every 3 weeks.. Overall, 176 patients were randomised. After 124 events, median PFS was not significantly improved with ombrabulin vs placebo (5.65 vs 5.45 months; HR 0.948; 60% CI 0.813-1.106; one-sided P=0.39). The two groups showed similar overall survival (median 11.0 months in both groups), objective response rate (32% ombrabulin; 31% placebo) and safety profiles.. This study did not meet its primary endpoint of improving PFS by adding ombrabulin to a taxane-platinum regimen for first-line treatment of metastatic NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platinum; Serine; Taxoids; Treatment Outcome

The in vivo combination effect of AC-7700, a novel combretastatin A-4 derivative, and cisplatin (CDDP) was examined. The combination of AC-7700 and CDDP increased antitumor activity against murine colon 26 tumor in mice and cured the mice. This combination effect was found over wide dosage ranges of AC-7700 (20-80 mg/kg) and CDDP (2.5-5 mg/kg). Moreover, this combination augmented antitumor activity against murine S180 and M109 tumors, and human LX-1 and LS180 tumor xenografts in mice. The effect was the strongest when AC-7700 and CDDP were administered simultaneously. To study this combination effect, we measured the concentrations of CDDP in tumors, plasma and kidneys of the mice with colon 26 tumor. In the combination with AC-7700, the concentration of CDDP in the tumors increased from 0.5 to 96 h after administration, but did not change or decrease in plasma or kidneys. Against human LS180 xenografts in mice, the combination similarly increased the concentration of CDDP in the tumors. These results suggest that AC-7700 may specifically augment the accumulation of CDDP in tumors, and thus has the potential to be useful in combination chemotherapy with CDDP.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cisplatin; Colonic Neoplasms; Drug Administration Schedule; Humans; Lung Neoplasms; Mice; Mice, Inbred ICR; Mice, Nude; Sarcoma 180; Serine; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We previously reported that a novel combretastatin A-4 derivative, AC7700, has remarkable antitumour effects because of an irreversible stasis of tumour blood flow (TBF) and subsequent loss of nutrient supply to tumour tissue. Since early 2002, under the new designation AVE8062, AC7700 has undergone clinical trials in Europe and the US. Questions remain, however, concerning how AC7700 blocks TBF and why the TBF stasis does not recover. In this study, using a rat tumour LY80, a variant of Yoshida sarcoma, we examined whether TBF cessation after AC7700 administration is due to a direct action of the agent on tumour blood vessels. We constructed electrodes that can drop a small quantity of the drug solution directly at the site of blood flow measurement and inserted them subcutaneously and into the tumour. We compared the blood flow responses of normal vessels and tumour vessels after administration of 10-microl doses of various concentrations (0.2, 1, 10, and 50 mg ml(-1)) of the AC7700 solution. In addition, we assessed TBF stasis after i.v. and intra-arterial 10 mg x kg(-1) AC7700 administration in an LY80-induced kidney tumour. To determine why the TBF stasis is irreversible, we observed AC7700-induced changes in host arterioles and the tumour vascular network of the Sato lung carcinoma using a vital microscopic rat transparent chamber. Since an increase in tumour interstitial fluid pressure brings about a decrease in TBF, we also measured 10 mg x kg(-1) AC7700-induced changes in this pressure. The sensitivity of the blood flow response after intratumoral application of AC7700 was markedly higher in normal vessels relative to tumour vessels. Intra-arterial administration of AC7700 did not have stronger effects on TBF stasis than did i.v. administration. Intravital microscopy showed that AC7700 induced a powerful and long-lasting constriction of host arterioles, so that complete stasis of blood flow occurred in downstream vessels, which supplied blood to tumours. Owing to this stasis, the lumens of numerous tumour vessels narrowed or completely disappeared, and numerous erythrocytes stagnated in drainage vessels of the tumour vascular network. Haemolysis of these erythrocytes occurred after 2-3 h, resulting in complete thrombosis. There was no indication of reperfusion in vessels showing haemolysis. This haemolysis is thought to be the main cause for the irreversibility of TBF stasis. Since the tumour interstitial fluid pressure decreased after i.v. AC770

Topics: Animals; Arterioles; Blood Flow Velocity; Blood Pressure; Lung Neoplasms; Male; Microcirculation; Muscle, Smooth, Vascular; Neoplasm Transplantation; Rats; Sarcoma, Yoshida; Serine; Tumor Cells, Cultured; Vasoconstriction; Vasoconstrictor Agents

In a previous study, we used subcutaneous LY80 tumours (a subline of Yoshida sarcoma), Sato lung carcinoma, and methylcholanthrene-induced primary tumours, to demonstrate that a novel water-soluble combretastatin A-4 derivative, AC7700, abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour. In the present study, we investigated whether AC7700 acts in the same way against solid tumours growing in the liver, stomach, kidney, muscle, and lymph nodes. Tumour blood flow and the change in tumour blood flow induced by AC7700 were measured by the hydrogen clearance method. In a model of cancer chemotherapy against metastases, LY80 cells (2x10(6)) were injected into the lateral tail vein, and AC7700 at 10 mg x kg(-1) was injected i.v. five times at intervals of 2 days, starting on day 7 after tumour cell injection. The number and size of tumours were compared with those in the control group. The change in tumour blood flow and the therapeutic effect of AC7700 on microtumours were observed directly by using Sato lung carcinoma implanted in a rat transparent chamber. AC7700 caused a marked decrease in the tumour blood flow of all LY80 tumours developing in various tissues and organs and growth of all tumours including lymph node metastases and microtumours was inhibited. In every tumour, tumour blood flow began to decrease immediately after AC7700 administration and reached a minimum at approximately 30 min after injection. In many tumour capillaries, blood flow completely stopped within 3 min after AC7700 administration. These results demonstrate that AC7700 is effective for tumours growing in various tissues and organs and for metastases. We conclude that tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma; Drug Screening Assays, Antitumor; Heart Neoplasms; Kidney Neoplasms; Liver Neoplasms, Experimental; Lung Neoplasms; Lymphatic Metastasis; Male; Neoplasm Transplantation; Organ Specificity; Prodrugs; Rats; Regional Blood Flow; Sarcoma, Yoshida; Serine; Skin Window Technique; Stomach Neoplasms; Tumor Cells, Cultured; Vasoconstrictor Agents