Limits...
Tumor hypoxia as a driving force in genetic instability.

Luoto KR, Kumareswaran R, Bristow RG - Genome Integr (2013)

Bottom Line: Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis.Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy.Hypoxia can also increase the rate of mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute, Radiation Medicine Program, Princess Margaret Cancer Centre (University Health Network), Toronto, ON, Canada. rob.bristow@rmp.uhn.on.ca.

ABSTRACT
Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination-mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells.

No MeSH data available.


Related in: MedlinePlus

Targeting of hypoxic cells in cancer treatment. Hypoxic cells can be quantitated in situ by staining for antibodies that measure uptake of nitroimidazole compounds (which are reduced in hypoxic environments and bind to SH-containing molecules such as glutathione and proteins); one such compound is pimonidazole (PIMO). These studies, in addition to direct measurements of pO2, have linked the proportion of hypoxic cells to aggressive tumor cell variants that are resistant to radiotherapy, chemotherapy and have an increased propensity for metastases. Direct targeting with agents that create DNA damage solely under hypoxic conditions (e.g. TH-302) or inhibit selective pathways activated in hypoxic cells (e.g. HIF1α and mTOR signaling) may improve the overall cell kill within a tumor volume when used alone or with radiotherapy or chemotherapy. Hypoxia may also lead to differential transcription or translation of DNA repair or replication genes which can reduce the function of the repair pathway. These repair-deficient hypoxic cells can be killed by agents that target remaining back-up pathways leading to cell death. Given the repair defect is secondary to the effects of hypoxia as opposed to a primary somatic or germline defect, this type of cell kill is denoted, “contextual synthetic lethality” given it is contextual on the local tumor microenvironment and varies depending on the metabolic state of the cancer cell.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4016142&req=5

Figure 4: Targeting of hypoxic cells in cancer treatment. Hypoxic cells can be quantitated in situ by staining for antibodies that measure uptake of nitroimidazole compounds (which are reduced in hypoxic environments and bind to SH-containing molecules such as glutathione and proteins); one such compound is pimonidazole (PIMO). These studies, in addition to direct measurements of pO2, have linked the proportion of hypoxic cells to aggressive tumor cell variants that are resistant to radiotherapy, chemotherapy and have an increased propensity for metastases. Direct targeting with agents that create DNA damage solely under hypoxic conditions (e.g. TH-302) or inhibit selective pathways activated in hypoxic cells (e.g. HIF1α and mTOR signaling) may improve the overall cell kill within a tumor volume when used alone or with radiotherapy or chemotherapy. Hypoxia may also lead to differential transcription or translation of DNA repair or replication genes which can reduce the function of the repair pathway. These repair-deficient hypoxic cells can be killed by agents that target remaining back-up pathways leading to cell death. Given the repair defect is secondary to the effects of hypoxia as opposed to a primary somatic or germline defect, this type of cell kill is denoted, “contextual synthetic lethality” given it is contextual on the local tumor microenvironment and varies depending on the metabolic state of the cancer cell.

Mentions: The success of anti-cancer therapies is currently challenged by increased local and systemic resistance of tumor cells residing in the hypoxic microenvironment. However, the hypoxic phenotype can also provide an opportunity to specifically target cells in the tumor microenvironment and improve the therapeutic index (e.g. kill more cancer cells than normal cells) (see Figure 4). The development of therapeutic agents that are selectively activated upon exposure to low oxygen is of great interest [32]. For example, tirapazamine and apaziquone, both bioreductive prodrugs that induce DNA damage, have been tested in Phase III clinical trials [32]. A newer compound, TH-302, is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM), which causes DNA damage under hypoxic/anoxic conditions [132]. The antitumor activity of TH-302 has been shown to be dose-dependent and decreased the hypoxic fraction in xenografts of varying histology. TH-302 also induces DNA damage (as measured by γ-H2AX) in hypoxic regions in vivo and can further kill cells through a time-dependent “bystander effect”. This compound is currently in Phase II-III clinical trials in combination with chemotherapy.


Tumor hypoxia as a driving force in genetic instability.

Luoto KR, Kumareswaran R, Bristow RG - Genome Integr (2013)

Targeting of hypoxic cells in cancer treatment. Hypoxic cells can be quantitated in situ by staining for antibodies that measure uptake of nitroimidazole compounds (which are reduced in hypoxic environments and bind to SH-containing molecules such as glutathione and proteins); one such compound is pimonidazole (PIMO). These studies, in addition to direct measurements of pO2, have linked the proportion of hypoxic cells to aggressive tumor cell variants that are resistant to radiotherapy, chemotherapy and have an increased propensity for metastases. Direct targeting with agents that create DNA damage solely under hypoxic conditions (e.g. TH-302) or inhibit selective pathways activated in hypoxic cells (e.g. HIF1α and mTOR signaling) may improve the overall cell kill within a tumor volume when used alone or with radiotherapy or chemotherapy. Hypoxia may also lead to differential transcription or translation of DNA repair or replication genes which can reduce the function of the repair pathway. These repair-deficient hypoxic cells can be killed by agents that target remaining back-up pathways leading to cell death. Given the repair defect is secondary to the effects of hypoxia as opposed to a primary somatic or germline defect, this type of cell kill is denoted, “contextual synthetic lethality” given it is contextual on the local tumor microenvironment and varies depending on the metabolic state of the cancer cell.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016142&req=5

Figure 4: Targeting of hypoxic cells in cancer treatment. Hypoxic cells can be quantitated in situ by staining for antibodies that measure uptake of nitroimidazole compounds (which are reduced in hypoxic environments and bind to SH-containing molecules such as glutathione and proteins); one such compound is pimonidazole (PIMO). These studies, in addition to direct measurements of pO2, have linked the proportion of hypoxic cells to aggressive tumor cell variants that are resistant to radiotherapy, chemotherapy and have an increased propensity for metastases. Direct targeting with agents that create DNA damage solely under hypoxic conditions (e.g. TH-302) or inhibit selective pathways activated in hypoxic cells (e.g. HIF1α and mTOR signaling) may improve the overall cell kill within a tumor volume when used alone or with radiotherapy or chemotherapy. Hypoxia may also lead to differential transcription or translation of DNA repair or replication genes which can reduce the function of the repair pathway. These repair-deficient hypoxic cells can be killed by agents that target remaining back-up pathways leading to cell death. Given the repair defect is secondary to the effects of hypoxia as opposed to a primary somatic or germline defect, this type of cell kill is denoted, “contextual synthetic lethality” given it is contextual on the local tumor microenvironment and varies depending on the metabolic state of the cancer cell.
Mentions: The success of anti-cancer therapies is currently challenged by increased local and systemic resistance of tumor cells residing in the hypoxic microenvironment. However, the hypoxic phenotype can also provide an opportunity to specifically target cells in the tumor microenvironment and improve the therapeutic index (e.g. kill more cancer cells than normal cells) (see Figure 4). The development of therapeutic agents that are selectively activated upon exposure to low oxygen is of great interest [32]. For example, tirapazamine and apaziquone, both bioreductive prodrugs that induce DNA damage, have been tested in Phase III clinical trials [32]. A newer compound, TH-302, is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM), which causes DNA damage under hypoxic/anoxic conditions [132]. The antitumor activity of TH-302 has been shown to be dose-dependent and decreased the hypoxic fraction in xenografts of varying histology. TH-302 also induces DNA damage (as measured by γ-H2AX) in hypoxic regions in vivo and can further kill cells through a time-dependent “bystander effect”. This compound is currently in Phase II-III clinical trials in combination with chemotherapy.

Bottom Line: Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis.Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy.Hypoxia can also increase the rate of mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute, Radiation Medicine Program, Princess Margaret Cancer Centre (University Health Network), Toronto, ON, Canada. rob.bristow@rmp.uhn.on.ca.

ABSTRACT
Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination-mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells.

No MeSH data available.


Related in: MedlinePlus