Nefits of PDT-induced vascular shutdown as part of a combination therapy are discussed further below.PDT Based combination therapiesIt is increasingly evident that the next-generation of cancer therapeutics will comprise of combinatorial approaches that overcome intrinsic resistance pathways via non-overlapping and interactive mechanisms that enhance overall survival and reduce recurrence rates. PDT forms the basis of promising anti-cancer regimens because the mechanisms underlying photodamage are distinct from most chemo-, radio-, or biological therapies. Therefore, PDT based combination regimens can improve outcomes due to the potential for mechanistic cooperativity, wherein the effects of PDT potentiate the effects of subsequent treatments and vice-versa, leading to synergistic reductions in tumor volume while maintaining a manageable toxicity profile. Due to these advantages, rationally designed PDT based combination therapies may help to overcome light-based limitations posed by deep tissue because the effects of secondary, non-light based, therapies can lead to increased cytotoxicity in target tissues that were either sub-optimally or minimally impacted by PDT. A selected series of studies demonstrating the potential for rationally designed PDT based combinations to improve outcomes in deep tissue are discussed below. Numerous studies have demonstrated that the effectiveness of light-based combinations depends on mechanistic interactions between PDT, the subsequent therapy, and the disease being treated. In order to achieve synergism and impart an improved efficacy in deep tissue, PDT and the secondary therapy must induce interactive cytotoxic mechanisms in the target tissue whose consequences are greater than the additive effects of the individual modalities. Furthermore, the target tissue itself must also exhibit an amenable biological landscape to support any mechanistic cooperativity. This principle was highlighted as early as 1988, when Nahabendian et al. demonstrated disease and LDN193189 msds treatment specific interactions with HpD-PDT order SIS3 combined with either doxorubicin or cisplatin. It was found that treating BALB/c mice bearing EMT-6 tumor xenografts with HpD-PDT combined with doxorubicin led to a synergistic reduction in tumor burden and increased the depth of killing within the tumor. However, combining HpD-PDT with cisplatin led to an additive effect, and the authors noted that a significanthttp://www.thno.orgTheranostics 2016, Vol. 6, Issueproportion of the tumor was unaffected at depth for this regimen. In addition, RIF-1 tumors were not sensitive to either of the HpD-PDT based combinations, highlighting the importance of considering both the combination therapy as well as the disease being treated when designing comprehensive treatment regimens [183]. The sequence of component therapies in a larger combination also impacts the overall efficacy within deep tissue. For example, Zuluaga et. al. showed that mitomycin C treatment of mouse RIF-1 subcutaneous tumors prior to HpD-PDT was more effective at reducing tumor burden than vice-versa [184]. This finding has been echoed in a study published by our group demonstrating that BPD-PDT combined with carboplatin exhibited a sequence dependent synergism. Treating three-dimensional (3D) ovarian cancer nodules with carboplatin prior to BPD-PDT resulted in only an additive therapeutic effect, whereas a synergistic effect was observed when BPD-PDT preceded carboplatin [185]. This sequence depe.Nefits of PDT-induced vascular shutdown as part of a combination therapy are discussed further below.PDT Based combination therapiesIt is increasingly evident that the next-generation of cancer therapeutics will comprise of combinatorial approaches that overcome intrinsic resistance pathways via non-overlapping and interactive mechanisms that enhance overall survival and reduce recurrence rates. PDT forms the basis of promising anti-cancer regimens because the mechanisms underlying photodamage are distinct from most chemo-, radio-, or biological therapies. Therefore, PDT based combination regimens can improve outcomes due to the potential for mechanistic cooperativity, wherein the effects of PDT potentiate the effects of subsequent treatments and vice-versa, leading to synergistic reductions in tumor volume while maintaining a manageable toxicity profile. Due to these advantages, rationally designed PDT based combination therapies may help to overcome light-based limitations posed by deep tissue because the effects of secondary, non-light based, therapies can lead to increased cytotoxicity in target tissues that were either sub-optimally or minimally impacted by PDT. A selected series of studies demonstrating the potential for rationally designed PDT based combinations to improve outcomes in deep tissue are discussed below. Numerous studies have demonstrated that the effectiveness of light-based combinations depends on mechanistic interactions between PDT, the subsequent therapy, and the disease being treated. In order to achieve synergism and impart an improved efficacy in deep tissue, PDT and the secondary therapy must induce interactive cytotoxic mechanisms in the target tissue whose consequences are greater than the additive effects of the individual modalities. Furthermore, the target tissue itself must also exhibit an amenable biological landscape to support any mechanistic cooperativity. This principle was highlighted as early as 1988, when Nahabendian et al. demonstrated disease and treatment specific interactions with HpD-PDT combined with either doxorubicin or cisplatin. It was found that treating BALB/c mice bearing EMT-6 tumor xenografts with HpD-PDT combined with doxorubicin led to a synergistic reduction in tumor burden and increased the depth of killing within the tumor. However, combining HpD-PDT with cisplatin led to an additive effect, and the authors noted that a significanthttp://www.thno.orgTheranostics 2016, Vol. 6, Issueproportion of the tumor was unaffected at depth for this regimen. In addition, RIF-1 tumors were not sensitive to either of the HpD-PDT based combinations, highlighting the importance of considering both the combination therapy as well as the disease being treated when designing comprehensive treatment regimens [183]. The sequence of component therapies in a larger combination also impacts the overall efficacy within deep tissue. For example, Zuluaga et. al. showed that mitomycin C treatment of mouse RIF-1 subcutaneous tumors prior to HpD-PDT was more effective at reducing tumor burden than vice-versa [184]. This finding has been echoed in a study published by our group demonstrating that BPD-PDT combined with carboplatin exhibited a sequence dependent synergism. Treating three-dimensional (3D) ovarian cancer nodules with carboplatin prior to BPD-PDT resulted in only an additive therapeutic effect, whereas a synergistic effect was observed when BPD-PDT preceded carboplatin [185]. This sequence depe.
