Minimal PK/PD model for simultaneous description of the maximal tolerated dose and metronomic treatment outcomes in mouse tumor models.

PURPOSE: Metronomic chemotherapy (MC) is a promising approach where, in contrast to the conventional maximal tolerated dose (MTD) strategy, regular fractionated doses of the drug are used. This approach has proven its efficacy, although drug dosing and scheduling are often chosen empirically. Pharmacokinetic/pharmacodynamic (PK/PD) models provide a way to choose optimal protocols with computational methods. Existing models are usually too complicated and are valid for only a subset of drug schedules. To address this issue, we propose herein a simple model that can describe MC and MTD regimens simultaneously. METHODS: The minimal model comprises tumor suppression due to antiangiogenic drug effect together with a cell-kill term, responsible for its cytotoxicity. The model was tested on data obtained on tumor-bearing mice treated with gemcitabine in ether MTD, MC, or combined (MTD + MC) regimens. RESULTS: We conducted a number of tests in which data were divided in various ways into training and validation sets. The model successfully described different trends in the MTD and MC regimens. With parameters obtained by fitting the model to MTD data, the simulations correctly predicted trends in both the MC and combined therapy groups. CONCLUSION: Our results demonstrate that the proposed model presents a minimal yet efficient tool for modeling outcomes in different treatment regimens in mice. We hope that this model has the potential for use in clinical practice in the development of patient-specific chemotherapy scheduling protocols based on observed treatment response.

PDT with genetically encoded photosensitizer miniSOG on a tumor spheroid model: A comparative study of continuous-wave and pulsed irradiation.

BACKGROUND: Therapeutic effects of PDT depend on many factors, including the amount of singlet oxygen, localization of photosensitizer and irradiation protocol. The present study was aimed to compare the cytotoxic mechanisms of PDT under continuous-wave (CW) and pulsed irradiation using a tumor spheroid model and a genetically encoded photosensitizer miniSOG. METHODS: 1O2 detection in miniSOG and flavin mononucleotide (FMN) solutions was performed. Photobleaching of miniSOG in solution and in HeLa tumor spheroids was analyzed. Tumor spheroid morphology and growth and the cell death mechanisms after PDT in CW and pulsed modes were assessed. RESULTS: We found a more rapid 1O2 generation and a higher photobleaching rate in miniSOG solution upon irradiation in pulsed mode compared to CW mode. Photobleaching of miniSOG in tumor spheroids was also higher after irradiation in the pulsed mode. PDT of spheroids in CW mode resulted in a moderate expansion of the necrotic core of tumor spheroids and a slight inhibition of spheroid growth. The pulsed mode was more effective in induction of cell death, including apoptosis, and suppression of spheroid growth. CONCLUSIONS: Comparison of CW and pulsed irradiation modes in PDT with miniSOG showed more pronounced cytotoxic effects of the pulsed mode. Our results suggest that the pulsed irradiation regimen enables enhanced 1O2 production by photosensitizer and stimulates apoptosis. GENERAL SIGNIFICANCE: Our results provide more insights into the cellular mechanisms of anti-cancer PDT and open the way to improvement of light irradiation protocols.

Pulse mode of laser photodynamic treatment induced cell apoptosis.

One of the factors limiting photodynamic therapy (PDT) is hypoxia in tumor cells during photodynamic action. PDT with pulse mode irradiation and appropriate irradiation parameters could be more effective in the singlet oxygen generation and tissue re-oxygenation than continuous wave (CW) mode. We theoretically demonstrate differences between the cumulative singlet oxygen concentration in PDT using pulse mode and CW mode of laser irradiation. In vitro experimental results show that photodynamic treatment with pulse mode irradiation has similar cytotoxicity to CW mode and induces mainly cell apoptosis, whereas CW mode induces necrotic cell death. We assume that the cumulative singlet oxygen concentration and the temporal distribution of singlet oxygen are important in photodynamic cytotoxicity and apoptosis initiation. We expect our research may improve irradiation protocols and photodynamic therapy efficiency.