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Oncology Intelligence

VDA
VDA/VTA
VDA(7)

A VTA is an antiangiogenic that stops tumors from producing new blood vessels, whereas a VDA disrupts established tumor vasculature.(1) The development of VTAs has typically concentrated on anti-angiogenic approaches such as inhibition of specific PTKs involved in tumor neovascularization. VTAs can also result in tumor cell necrosis and secondary tumor cell death, however the observed effects may not be as rapid as with a VDA.(1)
Unlike anti-angiogenic drugs, VDAs damage established tumor blood vessels.(2) VDAs can be small-molecule or ligand-based. VDAs destroy existing tumor vasculature.(3) VDAs fall into two main classes that both increase permeability of tumor vasculature: The molecular target of CA4 is clearly microtubules. It binds to the colchicine binding site in tubulin and depolymerizes microtubules, but is less toxic than colchicine. So far, DMXAA has not exhibited the high anti-tumor efficacy in humans.(4)
VDAs are characterized by their ability to cause a rapid and pronounced shutdown of blood flow to solid tumors by causing the endothelial cells, the cells that line the inside of blood vessels, to change shape and collapse. Selectivity over normal tissue can arise from the difference between the rapidly proliferating nature of the cancer cells and their dependence on tubulin for maintaining the cellular integrity. Some agents may be pro-apoptotic molecules and mitotic inhibitors at low nanomolar concentrations while exhibiting vascular disruption effects at a different drug concentration.(1)
Metal chelators can act as VTAs, such as tetrathiomolybdate. The most prominent class of VTAs are the taxanes: Taxol, Taxotere, larotaxel, ortataxel, milataxel, IDN-5390, tesetaxel, and TPI 2879. Another class of VTAs are the epothilones: sagopilone, patupilone, ABJ879, KOS-862, fludelone, BMS-317505, Ixempra, and KOS1584.(5) Other VTAs include quinazolines and similar compounds: Zactima, canertinib, Tarceva, Iressa, brivanib, Tykerb, tandutinib, Recentin, CP-724714; quinolones: bosutinib, pelitinib, neratinib and E-7080; pyrimidines: Sprycel, Gleevec, Tasigna, pazopanib, CYC-116, PKI166, AEE788 and TTI-237; Oxindoles: Tsu-68, semaxanib and Sutent; and urea and thioureas: sorafenib, MGCD-265, ABT-869. Still other VTAs classified into separate categories include fumagillins (TNP-470 and CKD-732), pthalimides (Revelmid, apremilast, Thalidomid, pomalidomide), peptidics (celengetide and tryprostatin A), and staurosporins (enzastaurin, lestaurtinib, MKC-1 10, and midostaurin). Others that do not fall into a simple category based on core-type include: vatalanib, motesanib, axitinib, TTI-237, fenretinide, murbritinib, E-7820, PF-2431066, and tasquinimod. Mabs that have been reported to have antiangiogenic properties include: Alacizumab, Vitaxin, Lucentis, volociximab, Erbitux, Vectibix, matuzumab, Herceptin, and Avastin. The aptamer Macugen has also been shown to be a VTA. MMPs (Marimastat, prinomastat, and neovastat) are also reported as VTAs. Lastly, there are several copper chelating agents that have been investigated as VTA's or anti-angiogenesis agents including Coprexa, ATN-224, Penicillamine, and Trientine. The current status of Coprexa appears to be that development has been discontinued.(1) Epothilones prevent cancer cells from dividing by interfering with tubulin.(6) Epothilone B has also been shown to induce tubulin polymerization into microtubules without the presence of GTP. Epothilone B also causes cell cycle arrest at the G2-M transition phase. One epothilone analog, ixabepilone, was approved in October 2007 by the FDA for BC no longer responding to currently available chemotherapies. In November 2008, the EMEA has refused a marketing authorization for Ixabepilone.(6)

Drugs/Indications
Trials Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
bacteriopheophorbide monolysine taurine WST-11 Tookad; Stakel Steba  P3: PC; P2: NSCLC (terminated), cholangiocarcinoma (terminated); P1/2: RCC trials
fosbretabulin CS-A4 Zybrestat Oxigene P3: thyroid; P2: NSCLC, ovarian, neuroendocrine, HNN; P1/2: CRC; P1: solid trials
vinflunine Javlor Pierre Fabre Medicament P3: BC, HNN, urethral; P2/3: stomach; P2: transition, SCLC, NSCLC, PC, penile; P1: solid, bladder trials
NGR015 NGR-hTNF Molmed P3: mesothelioma; P2: CRC, HCC, ovarian, SCLC, solid trials
combretastatin A1  OXi4503 Oxigene P2/3: thyroid; P2: solid; P1: HCC, AML trials
darinaparsin  SP-02L  ZIO-101  Zinapar Solasia P2: HCC, MM, hem, bone, NHL; P1: lymphoma, solid trials
ombrabulin AVE8062 AC7700, RPR258063 Sanofi P2: sarcoma; P2: solid NSCLC, ovarian trials
verubulin MPC-6827 EP-90745, MX 128495 Azixa Myriad P2: GBM, melanoma; P1: solid, BC trials
IMO-2055 Peregrine P2: RCC; P1: CRC, NSCLC trials
BNC105 Bionomics P2: RCC, mesothelioma trials
TL139 Pfizer P2: mesothelioma trials
VB-111 GT-111 Vascular P2: GBM, thyroid, RCC, NET, ovarian; P1: solid trials
ZD6126 AstraZeneca P2: CRC, RCC trials
crolibulin EPC-2407 MX 2407, MX116407 EpiCept P1/2: thyroid, solid; P1: lymphoma trials
melflufen Oncopeptides P1/2: MM trials
BAL101553 BAL27862 Basilea P1/2: solid trials
XMT-1107 Mersana P1: solid trials
KML-001 noncorporate P1: NSCLC trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
vadimezan ASA404 NSC 640488 Antisoma Discontinued; P3: NSCLC; P2: ovarian, PC; P1: solid trials
soblidotin TZT-1027 Last trial 2003; P2: NSCLC, sarcoma trials
  ATN-161 Ac-PHSCN-NH2 Attenuon Last new trials in 2006; P2 (terminated): RCC; P1/2: brain trials
CYT997 YM  terminated; P2: MM; P1/2: GBM trials
TNP-470 terminated; P2: pancreatic trials
indibulin ZIO-301 Ziopharm Last new trial 2008; P1/2: BC, solid trials
INNO-105 Innovive Pharmaceuticals Last new trial 2005; P1: solid trials
denibulin MN-029 MediciNova Failed -- trials reported but unknown; P1: solid trials reported but unknown



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References

1. Sebahar PR, Willardsen JA, Anderson MB. Anticancer Agents: VTA or VDA. Current Bioactive Compounds. 2009;5(1):79-97.

2. Kim S, Peshkin L, Mitchison TJ. Vascular disrupting agent drug classes differ in effects on the cytoskeleton. PLoS One. 2012;7(7):e40177.

3. Teoh DG, Secord AA. Antiangiogenic therapies in epithelial ovarian cancer. Cancer Control. 2011;18(1):31-43.

4. Schwartz EL. Antivascular actions of microtubule-binding drugs. Clinical Cancer Research. 2009;15(8):2594-601.

5. Fumoleau P, Coudert B, Isambert N, Ferrant E. Novel tubulin-targeting agents: anticancer activity and pharmacologic profile of epothilones and related analogues. Annals of oncology. 2007;18(suppl 5):v9-v15.

6. Epothilone. [cited]; Available from: http://en.wikipedia.org/wiki/Epothilone.

7. Regulation_of_gene_expression. [cited]; Available from: http://en.wikipedia.org/wiki/Regulation_of_gene_expression.