#
# arev:/usr/local/unicat/unireq/beamreq/req00167.txt
# UNICAT Member Beam Time Request  #167

# created Thu Mar 08 20:37:43 CST 2001
#

collaboration:
	No

collaborator+Pete:
	on

contact:
	boukarih@mail.nih.gov

days:
	3

description:
	Tubulin protein polymers (microtubules) are central to cell division and consequently are the target of many anti-cancer drugs. Recently, a new class of VINCA domain natural-product drugs such as Dolastatin, Cryptophysin and Hemiasterlin have been found, and are being tested in preclinical and early clinical trials. These novel compounds are known to destabilize microtubules and to induce tubulin ring polymers. Electron micrographs, dynamic light scattering, and SANS data reveal single-walled rings with diameters ranging from 27 to 47 nm depending on the drug. In a first series of complementary USAXS experiments performed at the UNICAT beamline the measurements indicated, surprisingly, the formation of sizable monodisperse aggregates (~7 microns) presumably from these rings. However, a follow-up experiment revealed the formation of gas bubbles in the solution, which hindered the interpretation of the new measurements. Additional extensive tests showed that these bubbles result from an unexpected X-ray induced chemistry of the DiMethylSulfoxide (DMSO) solvent present in the solutions.  Comparison of the solutions used in the first series of USAXS experiments with those used recently indicates that the new solutions had a four times higher concentration of DMSO, explaining therefore the different outcome of the two sets of measurements. In the present proposed experiments we plan to remove completely the DMSO from the solutions and perform USAXS experiments to verify our previous results and address the issue of the gas bubbles. We will use Dolastatin as well as other drugs with solutions prepared with different parameters (pH and ionic strength) to characterize the structuture of these aggregates.  Because of the size ranges of these aggregates USAXS is the appropriate technique to probe the aggregation process induced by these important new tubulin-binding drugs. 

equipment+required:
	USAXS Instrument only

experiment:
	USAXS studies of drug-induced tubulin ring polymers 

foreign+nationals:
	

hazards:
	No Hazards

minimumdays:
	2

name:
	Hacene Boukari

nonmembers:
	D. L. Sackett (NICHD, NIH, Bethesda, Maryland). H. Boukari (NICHD, NIH, Bethesda, Maryland). R. J. Nossal (NICHD, NIH, Bethesda, Maryland). 

station:
	33ID-D

unacceptable+dates:
	May 24 to May 31
	June 30 to July 05



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