Page 248 - 2014 Printable Abstract Book
P. 248
chemotherapeutic agents like carboplatin, irinotecan and TMZ showed synergistic effects when
combination index was calculated in 3 GBM tumor cell lines and 8 GBM stem cell lines. However, the
therapeutic efficacy of TMZ combination was greater than MLN0128 combination with either carboplatin
or irinotecan. Moreover, similar TMZ chemosensitivity was observed in MGMT non-methylated, TMZ in-
sensitive GBM stem cells and MGMT methylated GBM cells. These findings support the rationale for
clinical testing of MLN0128 in patients with GBM to provide insight towards optimizing therapeutic
efficacy of mTOR kinase inhibitors with standard care.
(PS4-23) New DNA-binding radioprotectors which repair transient radiation-induced DNA lesions. Pavel
3
1
2
1
N. Lobachevsky, PhD ; Andrea Smith, PhD ; Colin Skene, PhD ; Robert F. Anderson, PhD ; Jonathan M.
2
1
1
White, PhD ; Roger F. Martin, Peter MacCallum Cancer Centre, Melbourne, Australia ; Bio21 Institute and
2
University of Melbourne School of Chemistry, Melbourne, Australia ; and Department of Chemistry
3
University of Auckland, Auckland, New Zealand
Whilst an extensive understanding the enzymic repair of chemically stable DNA lesions has
accumulated over many decades, non-enzymic chemical repair of initial transient DNA lesions that are
precursors of stable DNA damage also plays a role in ameliorating the impact of a hostile environment on
cellular DNA. For example, Milligan and co-workers have drawn attention to the favourable oxidation
potential of tyrosine, and its abundance in nucleosomal proteins, as the basis for repair of transient
oxidising species. A similar mechanism accounts for the activity of new DNA-binding radioprotecting drugs
that we have developed over more than a decade. Pulse radiolysis studies indicate these DNA-binding
antioxidants repair transient radiation-induced lesions in DNA, by charge transfer. Our overall goal is to
develop topical radioprotectors to selectively delivered to normal tissues “at risk” in cancer radiotherapy
patients, for example oral mucosa. The initial lead drug of this series, methylproamine, shares the
bibenzimidazole structural feature with the commercially-available fluorescent DNA dyes Hoechst 33342
and 33258. As well as protection against the radiation-induced decrease in clonogenic survival in vitro,
the drugs also reduce the level of radiation-induced g-H2AX foci, consistent with the mechanism of
radioprotection involving attenuation of initial radiation-induced DNA damage. The clinical potential of
methylproamine is limited by its cytotoxicity, but an extensive lead optimisation program (> 150 new
analogues) has identified several new analogues with reduced cytoxicity, without compromise of
radioprotective activity. The innate drug fluorescence has facilitated the development of topical
formulations to optimise delivery of the drugs to mouse oral mucosa. The best of the new
drug/formulation combinations have been shown to confer topical radioprotection of mouse oral mucosa.
The radiobiological model used, developed by Professor Wolfgang Doerr in Dresden, involves irradiation
of a small area (3mm x3mm) of the ventral surface of mouse tongue with low energy (25keV) X-rays.
Ulceration about 10 days post-irradiation is confined to the ventral surface, so feeding is not impeded.
We are now in the closing stages of selecting a final lead for clinical studies.
246 | P a g e
combination index was calculated in 3 GBM tumor cell lines and 8 GBM stem cell lines. However, the
therapeutic efficacy of TMZ combination was greater than MLN0128 combination with either carboplatin
or irinotecan. Moreover, similar TMZ chemosensitivity was observed in MGMT non-methylated, TMZ in-
sensitive GBM stem cells and MGMT methylated GBM cells. These findings support the rationale for
clinical testing of MLN0128 in patients with GBM to provide insight towards optimizing therapeutic
efficacy of mTOR kinase inhibitors with standard care.
(PS4-23) New DNA-binding radioprotectors which repair transient radiation-induced DNA lesions. Pavel
3
1
2
1
N. Lobachevsky, PhD ; Andrea Smith, PhD ; Colin Skene, PhD ; Robert F. Anderson, PhD ; Jonathan M.
2
1
1
White, PhD ; Roger F. Martin, Peter MacCallum Cancer Centre, Melbourne, Australia ; Bio21 Institute and
2
University of Melbourne School of Chemistry, Melbourne, Australia ; and Department of Chemistry
3
University of Auckland, Auckland, New Zealand
Whilst an extensive understanding the enzymic repair of chemically stable DNA lesions has
accumulated over many decades, non-enzymic chemical repair of initial transient DNA lesions that are
precursors of stable DNA damage also plays a role in ameliorating the impact of a hostile environment on
cellular DNA. For example, Milligan and co-workers have drawn attention to the favourable oxidation
potential of tyrosine, and its abundance in nucleosomal proteins, as the basis for repair of transient
oxidising species. A similar mechanism accounts for the activity of new DNA-binding radioprotecting drugs
that we have developed over more than a decade. Pulse radiolysis studies indicate these DNA-binding
antioxidants repair transient radiation-induced lesions in DNA, by charge transfer. Our overall goal is to
develop topical radioprotectors to selectively delivered to normal tissues “at risk” in cancer radiotherapy
patients, for example oral mucosa. The initial lead drug of this series, methylproamine, shares the
bibenzimidazole structural feature with the commercially-available fluorescent DNA dyes Hoechst 33342
and 33258. As well as protection against the radiation-induced decrease in clonogenic survival in vitro,
the drugs also reduce the level of radiation-induced g-H2AX foci, consistent with the mechanism of
radioprotection involving attenuation of initial radiation-induced DNA damage. The clinical potential of
methylproamine is limited by its cytotoxicity, but an extensive lead optimisation program (> 150 new
analogues) has identified several new analogues with reduced cytoxicity, without compromise of
radioprotective activity. The innate drug fluorescence has facilitated the development of topical
formulations to optimise delivery of the drugs to mouse oral mucosa. The best of the new
drug/formulation combinations have been shown to confer topical radioprotection of mouse oral mucosa.
The radiobiological model used, developed by Professor Wolfgang Doerr in Dresden, involves irradiation
of a small area (3mm x3mm) of the ventral surface of mouse tongue with low energy (25keV) X-rays.
Ulceration about 10 days post-irradiation is confined to the ventral surface, so feeding is not impeded.
We are now in the closing stages of selecting a final lead for clinical studies.
246 | P a g e
