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Simple Summary: The hypofractionated radiotherapy of cancer involves the application of a reduced number of larger doses per fraction than used in typical conventional radiation treatments. Tumors can also be treated with hyperthermia (heating at 40–45 °C), and although such heat treatments alone have no relevance as a cancer therapy, pre-clinical and clinical studies indicate that hyperthermia can enhance the effect of hypofractionated radiation. However, additional pre-clinical and large-scale clinical studies are needed to optimize and establish standard treatment protocols, as well as demonstrate the efficacy and safety of this combination. This review addresses some of these issues. The conventional radiation treatment of cancer patients has typically involved a large number of daily treatments with relatively low doses of radiation. However, improved technology has now resulted in the increased use of fewer radiation fractions at a high dose per fraction. This latter approach is often referred to as hypofractionated irradiation. While conventional radiation typically kills tumor cells through the production of DNA damage, treatments with higher doses per fraction have been suggested to also kill cells via the induction of vascular damage. Such vascular effects will also increase the level of adverse microenvironmental conditions, such as hypoxia and acidity, that already exist in tumors. Cells existing in these adverse microenvironmental conditions are resistant to radiation but actually sensitive to hyperthermia (heating at 40–45 °C) treatment. This suggests that the combination of hypofractionated radiation and heat may be a viable treatment approach. While there are preliminary pre-clinical and even clinical studies investigating this option, there are actually no data on the optimal application for the greatest therapeutic benefit. In this critical review, we will present the rationale for combining hypofractionated radiation with hyperthermia and discuss what has been done and what should be done to establish this combination as an effective cancer therapy option. [ABSTRACT FROM AUTHOR]

This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5–20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5–100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice. [ABSTRACT FROM AUTHOR]

Background/aim: Hypoxia-activated pro-drugs, such as TH-302, may kill hypoxic treatment-resistant tumor cells, but have failed in clinical trials. This may be related to variable levels of drug-activating reductases. Compounds such as bacteria-derived BE-43547, which target hypoxic cells independently of reductases, may be beneficial. This study characterized the in vitro potency and hypoxia selectivity of BE-43547 and TH-302., Materials and Methods: Tumor cells were exposed to different oxygenation levels in the presence/absence of drug, and survival was quantified using total cell number (BE-43547) or clonogenic survival (BE-43547 and TH-302) assays. Half-maximal inhibitory concentration (IC 50 ) values and the hypoxia-cytotoxicity-ratio (HCR: normoxic IC 50 /hypoxic IC 50 ) were determined from dose-response curves. Finally, both drugs were tested in spheroids exposed to 20% or 0% O 2 for 24 h followed by assessment of clonogenic survival., Results: BE-43547 was highly potent and displayed little inter-cell line variability. Strongly enhanced cytotoxicity was observed under oxygen-restricted conditions with HCR's of ~100 and ~20 after 24 h of treatment with 0 or 0.5% O 2 , respectively. Reducing treatment time somewhat reduced hypoxia selectivity. Hypoxia selectivity was observed regardless of whether the drug was added before or during the hypoxic challenge. TH-302 IC 50 values varied 10-fold under oxic conditions, whereas those of the anoxic-to-normoxic HCR varied from 15 to 88. Both BE-43547 and TH-302 were unable to completely sterilize anoxic incubated spheroids., Conclusion: BE-43547 is highly hypoxia-selective, and unlike TH-302, displayed minimal variability between cell lines, suggesting that BE-43547 targets a fundamental feature/target that is only present, or of survival importance, during hypoxia. Spheroid experiments suggested inadequate tissue penetrability, which may be overcome by designing novel drug analogs., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)