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Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
One approach that may achieve these goals is to combine chemotherapy with hyperthermia (the application of heat).
Hyperthermia can effect cells in many different ways.19 It is known that heat can alter the structure of endogenous molecules such as lipids, nucleotides and proteins. While these changes occur at the cellular level in all cells in the heated area, at a higher level vascular disruption also takes place, leading to vascular dysfunction and tissue eradication.25,26 However, as the vasculature is perfused the extent of hyperthermia is more moderate in the vessels, but nevertheless may result in better tumor perfusion.
Combining hyperthermia with chemotherapy frequently gives contrasting results in vitro and in vivo due to the ways in which hyperthermia effects the tumor microenvironment (see above). Cisplatin was found to reduce tumor growth more efficiently in mouse mammary and rat glioma tumors when applied simultaneously with hyperthermia,36 although renal damage in rats resulting from the combination treatment were heightened.37 No enhancements in the reduction of tumor growth were detected for the antimetabolites, vinblastine and etoposide (Fig. To improve treatment protocols and reduce the side effects of hyperthermia, heating can be applied regionally or only locally and, furthermore, by careful timing of the treatment, with respect to drug administration, additional enhancements are possible.
Continuously circulating a heated solution containing chemotherapeutic agents inside the peritoneal cavity, a technique known as hyperthermic intraperitoneal chemotherapy, allows fast drug delivery to the gastric region. In phase II clinical studies doxorubicin, ifosfamide and etoposide52 or etoposide and ifosfamide (Fig.
The application of small molecules applied with hyperthermia indicates the considerable potential of the approach in cancer therapy. Despite the development of macromolecular drug formulations for thermotherapy, notably liposomal formulations, small-molecule drugs not designed for use in combination with hyperthermia continue to be evaluated in clinical trials. The mechanism of tumor cell death induced by the compound appears to be the same as that of chlorambucil itself and involves DNA damage. Randomized clinical trials have demonstrated overall patient survival prolongation with hyperthermia-drug treatment regimens applied to a wide range of malignancies. Further improvements of this treatment strategy will undoubtedly involve the development of more efficient heat-responsive drugs. Although the concept of hyperthermia has existed for many years it has yet to become routinely used in the clinical management of cancer. 1 Different mechanisms of antitumor activity induced by local hyperthermia of tumors: loss of membrane integrity, upregulation of heat shock proteins, activation of immune cells, necrotic cell death and vessel destruction.
Such increased perfusion facilitates increased trafficking of immune cells including T cells and dendritic cells.27,28 The above-mentioned mechanisms may be differently balanced in specific tumor types as well as from patient to patient. Drug exposure to cells remains relatively stable in vitro whereas in malignant tissue it is affected by the changes of the tumor blood flow induced by hyperthermia.30 Nevertheless, early studies demonstrated that alkylating agents such as methyl methanesulfonate (Fig. 2 Structures of the alkylating agents methyl methanesulfonate (a), melphalan (b), cyclophosphamide (c), cisplatin (d) and carboplatin (e).

Indeed, the sequence and timing of chemotherapy and hyperthermia are critical for enhanced tumor reduction and it was shown for several drugs (cisplatin, melphalan and carboplatin, Fig. This approach was subsequently applied in clinical trials with cytoreductive surgery in gastric and ovarian carcinomas, in combination with cisplatin (Fig. 5)53 were applied together with regional hyperthermia and shown to improve local control in high-risk, soft-tissue sarcoma compared to chemotherapy alone (a four year overall survival of 59% was achieved with the latter combination compared to 40% for chemotherapy alone). However, the molecules described above were not originally designed to be applied with hyperthermia, indicating that more effective compounds could be developed. There are clinical advantages in using low molecular weight thermosensitive drugs that are selectively activated at the tumor site by the application of hyperthermia.
6 Structures of the fluorine-containing drugs rosuvastatin (a), fluticasone (b) and torcetrapib (c). 7 show encouraging in vivo properties,94–100 as yet, none have progressed to clinical trials. However, the mechanism of thermal activation remains unclear, although it would appear to involve increased solubility at the heated tumor site with concomitant cleavage of the fluorous chain at the ester linker.
However, in order to make a local hyperthermia a more powerful cancer treatment strategy all possible factors of the treatment must be optimized. We had taken this image on the internet we feel would be one of the most representative pictures for papasurvey com free cookie dough.
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Since heating tumors activates an immune response, at least in part by the upregulation of heat shock proteins, and since activity of some chemotherapeutics depend on heat shock proteins,29 it may suggest that these treatment strategies may act synergistically. 2) that simultaneous administration of drug and heat is optimal.39,40 As mentioned above, hyperthermia can modify the tolerance of a tumor to chemotherapy leading to thermotolerance, an adaptive survival response, induced by heat preconditioning, whereby cells become resistant to a subsequent lethal insult. These promising results led to large and randomized phase III clinical trials with the first completed study showing moderate toxicity including skin burns, but with the response rate more than doubling under hyperthermia (28.8 vs.
Initial attempts to adapt compounds to hyperthermia were based on the encapsulation of established drugs in liposomes with temperature-dependent drug release characteristics.
However, a significant proportion of the encapsulated doxorubicin in ThermoDox® is lost following intravenous administration61,62 and, consequently, alternative drug delivery systems have been developed.
In this context many highly fluorinated compounds have excellent thermomorphic properties77–79 and fluorine compounds already play an important role in medicinal chemistry.80–82 Numerous anticancer drugs such as 5-fluorouracil (Fig.
Some of the compounds were found to be strongly cytotoxic to human ovarian A2780 and A2780cisR cancer cell lines (the latter having acquired resistance to cisplatin) under normal conditions, i.e. When combined with a 30 minute hyperthermia signal a few minutes after injection tumor growth inhibition increases to 79%.
Compounds in which the fluorous chain is covalently linked to the drug via non-cleavable groups do not appear to be endowed with such extensive thermoresponsive activity. This optimization process is not trivial due to the difficulties associated with maintaining the optimum intra-tumor temperature,108,109 hyperthermia-induced drug targeting110 and selective drug activation by heat.

Temperature-sensitive compounds have recently been developed by covalently modifying drug and drug-like molecules with thermomorphic perfluorinated appendages. However, the largest effects of hyperthermia are believed to be on proteins as they undergo denaturation and aggregation at temperatures >39 °C. 4), in the treatment of malignant mesothelioma in combination with mitomycin C in phase II clinical trials,43–45 and in a phase III study on colorectal carcinoma employing 5-fluorouracil and leucovorin (Fig. A cationic thermoresponsive liposomal system incorporating doxorubicin and ammonium bicarbonate operates via an alternative mechanism. 4),83 rosuvastatin and fluticasone84 and torcetapib85 contain one or more fluorine atoms (Fig. Hence, the original thermoresponsive ruthenium complexes mentioned above were redesigned with the fluorous chain tethered to a pyridine ligand via an ester linkage (Fig. Nevertheless, multiple studies have shown that hyperthermia complements chemosensitization and the mechanism of action of this dual-therapy appears to be dependent on the particular mechanism of each chemotherapeutic compound. A tentative, generic mechanism concerning drug delivery and heat activation is shown in Fig. Lead thermoresponsive compounds have been validated in a pre-clinical model, displaying high tumor growth inhibition, with strong synergies observed between hyperthermia and the thermomorphic compounds. This leads to inhibition of many cellular processes such as cell cycle arrest, inactivation of protein synthesis and inhibition of DNA synthesis and repair, resulting in inhibition of proliferation and cell death.20–22 Other important cellular changes induced by hyperthermia include the destruction of the cytoskeleton, making cellular motility difficult, and enhanced degradation of proteins through the proteasome and lysosomal pathways.
Including a 42 °C heating cycle for 2 hours during the incubation period increased their cytotoxicity. 8).103 These ruthenium compounds display a remarkable selectivity to cancer cells in vitro when used in combination with a 2 hour hyperthermia treatment of 41 °C.
9 and, while the approach has thus far only been demonstrated on a limited number of compounds, it is not unreasonable to assume that it can be applied to almost any bioactive (anticancer) molecule. In addition, changes in cellular metabolism resulting in decreased availability of ATP and enhanced production of reactive oxygen species (ROS) have been described.23,24 All these cellular changes ultimately lead to the loss of cell membrane integrity.
However, further validation of this approach is still needed as fluorous-tagged compounds also display relevant therapeutic properties under normal conditions111–113 and to determine whether it has advantages over the well-established use of thermoresponsive macromolecular drug delivery systems, some of which are progressing through clinical trials. In the various cancer cell lines tested the compound is consistently more cytotoxic following hyperthermia. Notably, in non-cancerous human endothelial HEK-293 cells hyperthermia did not lead to such a large increase in cell growth inhibition with an observed IC50 value of 132 ?M. In the same cell lines chlorambucil was less cytotoxic when applied in combination with hyperthermia, and analogues in which the fluorous chain is replaced by a hydrocarbon chain do not show clear thermoresponsive behavior. Note that the logP values of the chlorambucil derivatives with fluorous chains are significantly higher (ca.

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