The 3-dimensional Structure Of Anticancer Drug-DNA Complexes Determined By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$264,358.00
Summary
Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents ....Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents act by poisoning the DNA binding enzyme topoisomerase. Crystallographic analysis will give us unequivocal answers at the atomic level as to the exact way in which the drug binds to DNA and how this binding differs between antitumour active and inactive compounds. We believe that a knowledge of the DNA binding mode of a class of intercalating anticancer drugs at the atomic level is valuable in guiding drug design within that class.Read moreRead less
The Structural Basis For The Action Of Anticancer DNA-intercalating Topoisomerase Poisons
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs ....Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs. Many of these drugs work by binding directly to DNA and poisoning the DNA-manipulating enzyme, topoisomerase. Our objective is to discover the molecular basis of how anticancer drugs act through their interaction with DNA and topoisomerase. We propose to use the successful X-ray crystallography methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of anti-tumour active drugs, to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. Crystallographic analysis provides unequivocal data, at near atomic resolution, of the nature of the molecular interactions which provide specificity and selectivity in drug-DNA complexes. This information will be a valuable guide in the further development of this important class of topoisomerase poisons as anticancer drugs. We will initiate structural studies of ternary complexes between the topoisomerase enzyme, DNA and anticancer drugs. The solution of the X-ray crystal structures of these ternary complexes will allow the design of new antitumour topoisomerase poisons to be put on a completely rational basis.Read moreRead less
Reflex Control Of Human Jaw Muscles By Periodontal Mechanoreceptors
Funder
National Health and Medical Research Council
Funding Amount
$405,173.00
Summary
An understanding of the functional connection between the jaw muscles and various receptor organs in and around the mouth is necessary to elucidate the process of chewing and its underlying rules. Unless the details of this functional connection in health and disease are thoroughly understood, the diagnosis and treatment of chewing related disorders will remain at the present state. For example: a We still do not know why chewing in edentulous subjects is less efficient and why the bite forces i ....An understanding of the functional connection between the jaw muscles and various receptor organs in and around the mouth is necessary to elucidate the process of chewing and its underlying rules. Unless the details of this functional connection in health and disease are thoroughly understood, the diagnosis and treatment of chewing related disorders will remain at the present state. For example: a We still do not know why chewing in edentulous subjects is less efficient and why the bite forces in these individuals immediately fall to about 20 % of the teethed value. Do jaw muscles in these subjects get weak because they get less support from the receptor organs around the teeth? a We still do not understand the cause-causes of the temporomandibular dysfunction (a painful disease involving jaw muscles) which forms 18.7 % of total dental patients consulted per week in South Australia. This South Australian study indicated that the current treatments (such as pain killers, night plates, massage) Ocures? only about the half of all patients. We cannot increase the success of the treatment if we do not fully understand the control mechanisms of chewing? It is expected that the results of this study will establish the functional connection between one of the most important receptor organs in the mouth (periodontal mechanoreceptors) to the jaw muscle motoneurons in subjects with healthy teeth and gums and will illustrate the importance of keeping the periodontium healthy for developing strong and smooth masticatory forces. This knowledge can also allow us to treat jaw related disorders by approaches that bring back normal operation of the system. For example, this knowledge may help us design active dentures that replace the missing support.Read moreRead less