Development Of DNA Phosphate Crosslinking Agents As Potential Anticancer Drugs
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leukaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. Alkylating agents are one of the most important classes of anticancer drug. They bind irreversibly to the bases in DNA and weld the two strands of the double helix together. This cross-link is a powerful block to DNA replication and leads to the death of cancer cells by the process of programmed cell death. Cancer cells generally become resistant to alkylating agents by invoking repair mechanisms that remove the drug from the DNA bases, a response which breaks the cross-link and returns the DNA to its normal state. In this project, we are developing a new type of alkylating agent that reacts not with the DNA bases but with the phosphate groups of the DNA backbone. By this means the strands of DNA can again be cross-linked but now the linkage is between parts of the DNA that cancer cells cannot separate. In this way, we hope to be able to devise new drugs that are resistant to the normal mechanisms of DNA repair so that they will be active against drug-resistant tumours.Read moreRead less
Peripheral Neuropathy And Pain: Role Of The Sphingosine Kinase-sphingosine 1-phosphate System
Funder
National Health and Medical Research Council
Funding Amount
$282,905.00
Summary
Understanding the neural mechanisms that generate pathological pain remains one of the essential goals for the development of effective treatments for pain, chronic pain with less side effects. Lipids are able to modulate pain perception. We will determine the role of a molecule named sphingosine 1-phosphate as a basis for the development of therapies for the treatment of neuropathic pain.
Dental caries (tooth decay) is initiated by demineralisation of tooth hard tissue by organic acids produced by dental plaque bacteria from dietary sugars. The disease is a major public health problem and has an estimated economic burden in Australia of over $1 billion p.a. being higher than that for any other dietary-related disease. We have discovered and patented a novel amorphous calcium fluoride phosphate that is stabilised by phosphopeptides from the bovine milk protein casein. These comple ....Dental caries (tooth decay) is initiated by demineralisation of tooth hard tissue by organic acids produced by dental plaque bacteria from dietary sugars. The disease is a major public health problem and has an estimated economic burden in Australia of over $1 billion p.a. being higher than that for any other dietary-related disease. We have discovered and patented a novel amorphous calcium fluoride phosphate that is stabilised by phosphopeptides from the bovine milk protein casein. These complexes, designated CPP-ACFP, have the potential to provide superior clinical efficacy in preventing dental caries and treating and repairing early stages of disease. The aims of this project therefore are (i) to develop topical formulations of CPP-ACFP for application to teeth to repair early stages of decay and (ii) to characterise the three-dimensional structure of the CPP-ACFP complexes. The significance of this work is that a superior and novel treatment for dental caries may be developed as well as providing insight into the structure of organically-stabilised amorphous calcium phosphate and its role in biomineralisation processes.Read moreRead less