fosbretabulin and Melanoma

The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy.. Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin.. Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma.. The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Carboplatin; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Esophageal Neoplasms; Female; Humans; Infusions, Intravenous; Life Expectancy; Lung Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Paclitaxel; Patient Selection; Stilbenes

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemokine CXCL12; Diphosphates; Endothelial Cells; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Neoplasms; Prodrugs; Stem Cells; Stilbenes; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

A series of novel cinnamic acyl sulfonamide derivatives (9a-16e) have been designed and synthesized and their biological activities were also evaluated as potential tubulin polymerization inhibitors. Among all the compounds, 10c showed the most potent growth inhibitory activity against B16-F10 cancer cell line in vitro, with an IC(50) value of 0.8μg/mL. Docking simulation was performed to insert compound 10c into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 10c with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cinnamates; Computer Simulation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Melanoma; Mice; Models, Molecular; Software; Structure-Activity Relationship; Sulfonamides; Swine; Tubulin; Tubulin Modulators

The purpose of this study was to develop a targeted combinatorial polymeric micelle system that can sequentially kill tumor vasculature and tumor cells and increase the anticancer efficacy. Toward this goal, αvβ3 integrin-targeting peptide (RGD) functionalized polymeric micelles (RFPMs) based on the use of poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) was developed. Doxorubicin was conjugated to the biodegradable PEG-PLA micelle core, and combretastatin A4 was physically encapsulated into micelles (RFPMs-DOX-CA4). The RFPMs-DOX-CA4 has a particle size of 29.2 ± 2.5nm with spherical shape and high encapsulation efficiency for both drugs (> 95%). The micelles exhibited sequential release kinetics for both drugs. Treatment with RFPMs-DOX-CA4 resulted in the sequential killing of endothelial cells and tumor cells in vitro. RFPMs displayed prolonged circulation time and more drug accumulation in solid tumor than unfunctionalized polymeric micelles (UFPMs). In B16-F10 tumor-bearing mice, RFPMs-DOX-CA4 showed stronger tumor growth inhibition and significantly higher survival rate compared with the other treatment groups. Treatment with RFPMs-DOX-CA4 caused a dramatic destruction of tumor vasculature and reduction of tumor cell proliferation in vivo. These results suggested that the integrated strategy can be exploited as a potential treatment modality for cancer.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Humans; Melanoma; Mice; Micelles; Polyethylene Glycols; Stilbenes

Two series of combretoxazolones including 3,4-diaryloxazolones (6) and 4,5-diaryloxazolones (7) were synthesized and evaluated for cytotoxicity and antitumor activity. Both series showed strong cytotoxicities against a variety of tumor cell lines. Compound 6g exhibited a significant antitumor activity in BDF1 mice bearing B16 murine melanoma cells with inhibition rates of 67 and 61% at 100 and 30 mg/kg/day, respectively.

Topics: Animals; Antineoplastic Agents; Biochemistry; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Melanoma; Mice; Mice, Inbred Strains; Oxazoles; Tumor Cells, Cultured

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) and combretastatin A4 phosphate (CA-4-P) markedly inhibit tumor blood flow in mice and are both currently in clinical trial. One of the challenges in clinical evaluation of antivascular agents is the monitoring of tumor blood flow inhibition in individual patients. This study investigates, using mouse models, whether a new marker for tissue hypoxia, (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (99mTc-labeled HL-91; Prognox)] has potential for the scintigraphic monitoring of tumor response to antivascular agents. Determination of radioactivity in dissected tissues 3 h after DMXAA (80 micromol/kg) or CA-4-P (227 micromol/kg) was injected indicated that both drugs inhibited blood flow (86RbCl uptake; 84 and 87%, respectively) and increased 99mTc-labeled HL-91 levels (350 and 300%, respectively) selectively in murine RIF-1 tumors. Planar imaging of 99mTc-labeled HL-91 3 h after DMXAA injection showed a dose-dependent increase in tumor levels above a threshold of 50 micromol/kg; this same threshold was observed for the inhibition of tumor blood flow (determined using Hoechst 33342). DMXAA also inhibited blood flow--and increased 99mTc-labeled HL-91 uptake--in MDAH-MCa-4 mouse mammary carcinomas and in NZMN10 human melanoma xenografts. Whether 99mTc-labeled HL-91 might also be useful as a biomarker for tumor cell killing was investigated by clonogenic assay of surviving cells 15 h after imaging 99mTc-labeled HL-91 in RIF-1 tumors. Log cell kill in individual tumors showed a statistically significant linear correlation (P < 0.001) with 99mTc-labeled HL-91 uptake after 60 micromol/kg (r2 = 0.79) and 70 micromol/kg (r2 = 0.44) but not at 80 micromol/kg DMXAA. The lack of correlation at high doses presumably reflects the insensitivity of the tumor-averaged 99mTc-labeled HL-91 signal to small regions in which tumor blood flow is preserved (which will limit log cell kill). The results indicate the potential of 99mTc-labeled HL-91 for the noninvasive imaging of tumor blood flow inhibition by antivascular drugs in humans.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Hypoxia; Fibrosarcoma; Humans; Mammary Neoplasms, Experimental; Melanoma; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Neoplasms, Experimental; Organotechnetium Compounds; Oximes; Radionuclide Imaging; Radiopharmaceuticals; Stilbenes; Xanthenes; Xanthones

A series of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds have been synthesized and evaluated as cytotoxic compounds and as antimitotic agents interacting with tubulin. The 2-phenyl-4-quinolones (22-30) with substituents (e.g. F, Cl, and OCH3) at C-6, C-7, and C-8 show, in general, potent cytotoxicity against human lung carcinoma (A-549), ileocecal carcinoma (HCT-8), melanoma (RPMI-7951), and epidermoid carcinoma of the nasopharynx (KB) and two murine leukemia lines (P-388 and L1210). Introduction of alkyl groups at N-1 or C-4 oxygen led to inactive compounds (35-43 and 50). In addition, compounds 24, 26, and 27 were evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. These compounds demonstrated the most marked effects in the screen on two colon carcinoma cell lines (COLO-205 and KM-20L2) and on a central nervous system tumor cell line (SF-539) with compound 26 the most potent of the three agents. Compounds 24, 26, and 27 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. The three agents also inhibited the binding of radiolabeled colchicine to tubulin, but this inhibition was less potent than that obtained with the natural products.

Topics: Animals; Antineoplastic Agents; Humans; Intestinal Neoplasms; Leukemia L1210; Leukemia P388; Lung Neoplasms; Melanoma; Mice; Molecular Structure; Nasopharyngeal Neoplasms; Quinolines; Quinolones; Software; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Tumor Cells, Cultured

A series of stilbenes has been prepared and tested for cytotoxicity in the five human cancer cell lines A-549 non-small cell lung, MCF-7 breast, HT-29 colon, SKMEL-5 melanoma, and MLM melanoma. The cis stilbenes 6a-f proved to be cytotoxic in all five cell lines, with potencies comparable to that of combretastatin A-4. These cytotoxic compounds were all potent inhibitors of tubulin polymerization. The corresponding trans stilbenes 7b-f were inactive as tubulin polymerization inhibitors and were significantly less cytotoxic in the five cancer cell lines. In the dihydro series, 8b, 8c, and 8f were inactive as tubulin polymerization inhibitors, while 8a, 8d, and 8e were less active than the corresponding cis compounds 6a, 6d, and 6e. The lack of tubulin polymerization inhibitory activity and cytotoxicity displayed by the phenanthrene 23b, which was synthesized as a conformationally rigid analogue of the lead compound 1, indicates that the activity of the stilbenes is not due to a totally planar conformation. Similarly, inactivity of the conformationally restricted analogue 26 suggests that the biologically active conformation of 1a resembles that of the cis alkene 1. Additional inactive compounds prepared include the benzylisoquinoline series 28-32 as well as the protoberberines 38 and 39. Shortening the two-carbon bridge of 1a to a one-carbon bridge in the diphenylmethane 20 resulted in a decrease in cytotoxicity and tubulin polymerization inhibitory activity. Although the corresponding benzophenone 18 was as active as 1a as a tubulin polymerization inhibitor, it was less cytotoxic than 1a, and the benzhydrol 19 was essentially inactive. With the exception of the amide 15c, which displayed low antitubulin activity, all of the phenylcinnamic acid derivatives 14a-c and 15a-f were inactive in the tubulin polymerization inhibition assay. The acid 14b and the ester 15a were cytotoxic in several of the cancer cell cultures in spite of their inactivity as tubulin polymerization inhibitors.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Colonic Neoplasms; Humans; Lung Neoplasms; Melanoma; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Tumor Cells, Cultured

An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a greater than 8a greater than 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a greater than 8a greater than 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Chemical Phenomena; Chemistry; Colchicine; Colonic Neoplasms; Humans; Lung Neoplasms; Melanoma; Molecular Structure; Polymers; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Tumor Cells, Cultured