From previous articles, we can see that most sensitization mechanisms not only increase the killing of tumor cells by drugs but also pose a potential threat of increased damage to normal cells. Previous studies have shown that HBO sensitizes chemotherapy mice, and the survival rate and average survival time of HBO chemotherapy mice are higher than those of pure chemotherapy group, indicating that HBO reduces the toxic side effects of chemotherapy drugs. However, this reasoning is not rigorous, because the tumor remission rate of the HBO chemotherapy group is originally higher than that of the pure chemotherapy group. At this time, the higher survival rate of the former than the latter does not indicate that HBO reduces the side effects of the drugs. In addition, hyperbaric oxygen can stimulate the reticular structure of the central nervous system, excite the cerebral cortex, and often be accompanied by pleasure. Therefore, it is also not rigorous to judge the side effects of chemotherapy drugs based solely on the mental status of mice. Therefore, in order to explore the effects of chemotherapy drugs on normal tissues under HBO conditions, specific indicators in the animal body should be measured. The study by Takiguchi et al. (2001) showed that the concentration of chemotherapy drugs in tumor tissues of HBO chemotherapy group animals was higher than that of pure chemotherapy group animals, and the concentration in normal tissue cells such as liver and kidney was also higher than that of the latter. This directly proves that chemotherapy drugs under HBO conditions increase damage to normal tissues. It can be seen that hyperbaric oxygen enhances the sensitivity of chemotherapy drugs to tumor tissue while increasing the damage of chemotherapy drugs to normal tissues. In addition, studies have shown that animal immune function is suppressed to varying degrees under HBO, and whether this effect synergizes with chemotherapy to cause damage to normal tissues remains to be explored. Therefore, it is necessary to explore a method to reduce the adverse factors of HBO chemotherapy to the body.
Animal experiments in domestic studies have shown that the retention of the hypoxic tissue imaging agent 99mTc-HL91 in mouse tumor tissues decreases after 25 minutes of hyperbaric oxygen (HBO) treatment. The number of hypoxic cells in the mouse tumors decreases, and oxygen metabolism significantly improves. With prolonged time in the hyperbaric oxygen chamber, the retention of the imaging agent 99mTc-HL91 in mouse tumor tissues gradually increases, and the effectiveness of HBO gradually decreases. The above experiments indicate that a high-oxygen state within tumors can be maintained for a certain period of time under normal pressure after HBO treatment.
There is a time difference in oxygen delivery between normal tissues and tumor tissues, with tumor tissue oxygen concentration decreasing slowly compared to normal tissue. As early as 1989, Vaupel and others proposed that due to various structural and functional differences between the blood vessels in tumor tissues and normal tissues, the vascular system in tumor tissues reacts slower and to a lesser extent to changes in oxygen concentration in the environment compared to normal tissues [14]. Zhang Shulun and colleagues from the Capital Institute of Pediatrics used microelectrodes to measure the changes in oxygen concentration in tumor and healthy muscle tissues of T-739 tumor-bearing mice when inhaling gas with different oxygen concentrations, confirming the differences in oxygen transport between tumor and normal tissues. Yu Hong and others (1997) suggested that by exploiting the differences in the changes of oxygen content caused by variations in oxygen concentration between tumor and normal tissues, a specific time period could be identified during which inhaling low oxygen concentrations leads to a faster decrease in oxygen content in normal tissues and a relatively lower oxygen concentration, while oxygen content in tumor tissues decreases slowly and oxygen concentration remains relatively higher [15]. If radiation therapy or chemotherapy is performed during this time period, it can be selective, maximizing the destruction of tumor tissues while protecting normal tissues, reducing side effects, and increasing therapeutic gain factors (TGF).
Anticancer drugs have a significantly higher cytotoxic effect on oxygen-rich cells than on hypoxic cells.
HBO sensitizes chemotherapy, as supported by corresponding literature and mechanisms. Anticancer drugs have a significantly higher cytotoxic effect on oxygen-rich cells than on hypoxic cells, with free radicals being the main reason for this sensitization. The use of drugs with quinone-like structures in chemotherapy is more common, as quinones can form semiquinone free radicals under the action of enzymes, which can react with oxygen to produce superoxide radicals, thereby causing cell damage. Many anticancer antibiotics and alkylating agents show particularly prominent effects. However, hypoxic cells are protected due to their high reduction potential in a hypoxic environment, where the formation of reactive oxygen species is not easy and can be easily quenched. Performing low-oxygen chemotherapy during a certain period of time after hyperbaric oxygen therapy results in a slow decrease in oxygen content and a relatively higher oxygen concentration in tumor tissues, making them relatively oxygen-rich cells, while normal tissues experience a faster decrease in oxygen content and a relatively lower oxygen concentration, making them hypoxic cells. Therefore, the toxicity of chemotherapy drugs to normal tissues may be reduced.
Low-oxygen radiation therapy after hyperbaric oxygen therapy can effectively kill tumor oxygen-rich cells while protecting normal tissues.
As mentioned earlier, there is a time difference in the transport of O2 between tumor and normal tissues. If low oxygen is inhaled shortly after HBO, this time difference becomes greater, making the selective action of chemotherapy drugs more convenient. Furthermore, since a high-oxygen state within tumors can be maintained for a certain period of time under normal pressure after HBO treatment, as long as the concentration and duration of low-oxygen inhalation after HBO is controlled, it is still possible to maintain a relatively higher oxygen partial pressure in tumor tissues. This has been confirmed in the combination of HBO with low-oxygen radiotherapy. This allows the chemotherapy drugs to maintain their enhanced sensitivity even when low concentrations of oxygen are inhaled. In recent years, Chinese scholars have proposed the concept of high-low oxygen radiotherapy, and preliminary experimental results have shown a significant improvement in the tumor tissue-killing effect and a reduction in normal tissue damage, resulting in a significant increase in the therapeutic gain factor (TGF). In a study by Ren Yangang et al. (2003), Lewis lung cancer mice were subjected to high-pressure oxygen followed by low-oxygen radiotherapy, and the results showed that it not only ensured the radiation-killing effect on tumors but also reduced the damage to normal tissues caused by radiation. However, so far, research on high-pressure oxygen followed by low-oxygen therapy has been limited to its combination with radiotherapy. Considering that chemotherapy, like radiotherapy, has a greater cytotoxic effect on oxygen-rich cells than on hypoxic cells, and chemotherapy is also an important clinical method for treating tumors, it is necessary to experimentally observe the effect of high-pressure oxygen followed by low-oxygen chemotherapy in order to provide new ideas for clinical tumor chemotherapy.
The time interval between hyperbaric oxygen therapy machine and low-oxygen therapy affects the therapeutic gain factor.
In the experiments of Ren Yangang et al. (2003), low-oxygen radiotherapy was performed 10 minutes after HBO. According to the literature mentioned above, if it is meaningful to perform low-oxygen chemotherapy after hyperbaric oxygen therapy, then this time interval should be as short as possible. However, due to limitations in clinical equipment conditions, it may not be feasible to perform low-oxygen therapy immediately after HBO treatment. Therefore, it is necessary to determine the effective time interval. If it is found that a longer time interval can still achieve a high therapeutic gain factor in low-oxygen chemotherapy, it would have greater clinical significance.
In tumor treatment with doxorubicin, leakage into the surrounding blood vessels can cause necrosis of local soft tissues, muscles, nerves, etc. Aktas studied the therapeutic effect of HBO using an animal model. Wistar rats were injected subcutaneously with doxorubicin 0.7ml (2 mg/ml) in the upper part of the right hind leg. The HBO group (n = 43) received HBO at 2.5 ATA for 80 minutes twice daily for a total of 28 days. The control group (n = 42) did not receive HBO treatment. The damage area was measured after 4 weeks, and no significant changes were observed between the two groups at 7 and 14 days. However, at 21 and 28 days, the HBO group showed a significantly smaller damage area compared to the control group. Among them, 16 rats fully recovered by day 40.
In conclusion, hyperbaric oxygen therapy has made significant progress in the treatment of malignant tumors and shows promising prospects for adjuvant therapy. It has gained recognition from scholars. However, there are still many issues that require further exploration in practical clinical applications. It is believed that in the near future, hyperbaric oxygen will be widely used as one of the comprehensive treatment methods for malignant tumors, playing an important role in enhancing therapeutic efficacy, reducing toxic side effects, and improving the quality of life for cancer patients.
Regarding the mechanism of how hyperbaric oxygen inhibits tumor growth, current research suggests the following factors:
Hyperbaric oxygen can increase oxygen free radicals, which have a cytotoxic effect on tumors. Malignant tumor cells have an imperfect antioxidant system, making them more susceptible to attack and death by free radicals. Therefore, hyperbaric oxygen has a promoting effect on normal cells but has a certain inhibitory effect on malignant tumors.
Hyperbaric oxygen can regulate immune function and enhance the cytotoxic effect of immune cells on tumors.
Tumors exhibit enhanced malignant behavior, particularly invasiveness, under hypoxic conditions. Hyperbaric oxygen can increase the oxygen partial pressure within the tumor.
Whether hyperbaric oxygen can block the increase in hypoxia-induced vascular endothelial growth factor and subsequent cancer metastasis remains to be confirmed.
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