Fever-range whole body thermotherapy combined with oxaliplatin: A curative regimen in a pre-clinical breast cancer model

Abstract

Purpose Studies were conducted to test whether fever-range whole body hyperthermia, rationally combined with oxaliplatin chemotherapy, would boost its efficacy without substantial toxicity. Materials and Methods The effect of heat on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumor cell line. In vivo, oxaliplatin was given with thermal therapy to rats bearing highly treatment-resistant MTLn3 mammary adenocarcinomas at various doses and times before, during, and after heating. Tumor growth, survival, and toxicity were measured to determine treatment outcome. Results Heating for 6h at 40°C halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24h before 6h of fever-range thermal therapy were completely, immunologically, cured while a further 11% regressed their primary tumor but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumor efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 hours before FR-WB-TT. Conclusions When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumors in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.

Aqueous Synthesis of Triphenylphosphine‐Modified Gold Nanoparticles for Synergistic In Vitro and In Vivo Photothermal Chemotherapy

“…The viability of cells treated with F-108@TPP-AuNP,b ut not subjected to the laser irradiation,w as reducedb y2 1%,p rimarily due to an enhanced mechanism of delivery.T he viability of cells incubated with F-108@TPP-AuNP and then subjected to laser irradiationd ecreased by ac onsiderable 58 %, demonstrating the pronounced and long-term effect of hyperthermia in conjunction with the delivery of TPP.S tudies have demonstrated that cancerc ells are sensitivet oi ncreasei nt emperature, with cells at 39 8Cw eakened and more sensitivet oc hemotherapy. [37] Treatmento fc ells with ac ytotoxic compound can result in a variety of cell fates including (i)necrosis, (ii)cytostasis and (iii)apoptosis. To determine which of these phenotypesw ere induced by TPP delivery, we treated HeLa cells for 4h with TPP-Au I Cl or F-108@TPP-AuNP and compared them to cells treated with no additive as controls.…”

Effector CD8+T cell IFN-γproduction and cytotoxicity are enhanced by mild hyperthermia

“…Furthermore, this study demonstrated that DC vaccination in combination with hyperthermia resulted in an increased infiltration of activated CD8 + cells into the tumor site accompanied by decreased infiltration of immune suppressive T reg cells, possibly creating an environment for improved tumor control (44). Recently long-term anti-tumor immunity was achieved in murine models; treatment with oxaliplatin chemotherapy followed twenty-four hours later by six hour whole body hyperthermia was able to cure all primary and metastatic tumors in 50% of MTLn3 tumor-bearing rats (13). …”

“…Based on a growing literature, it is apparent that the effect of hyperthermia on anti-tumor immunity is quite complex impacting various arms of the innate and adaptive immune response (11, 12). Excitingly, very recent studies in a clinically relevant animal model have demonstrated that adding hyperthermia to chemotherapy results in a curative therapy that is immunologically mediated (13). It has been widely reported that tumor infiltrating lymphocytes are essential for the inhibition of tumor growth and improved prognosis in various cancer types (14–19).…”

Combination of gemcitabine-containing magnetoliposome and oxaliplatin-containing magnetoliposome in breast cancer treatment: A possible mechanism with potential for clinical application

“…The cellular uptake of oxaliplatin and platinum-DNA adduct was measured as described previously [47] but with slight modifications. MCF-7 cells were divided into three groups with 5× 10 6 MCF-7 tumor cells per group and treated as follows: control group, 5% glucose solution at 37°C for 6 h; oxaliplatin group, 20 μg oxaliplatin/mL at 37°C for 6 h; OML group, 20 μg oxaliplatin/mL at 37°C for 6 h. Then, 1.6 mL of resuspension liquid of cell pellet with PBS in each group was divided into three parts and tested for a given parameter, as follows: 0.3 mL, cellular uptake; 0.2 mL, protein concentration; and 1.1 mL, DNA concentration and DNA adduct.…”