Introduction
Developing ways to prevent complications of chemotherapy drugs remains one of the most important issues in oncology.
In 1975, E.B. Burlakova and colleagues showed that chemotherapy agents, including cytostatics, alkylating agents, antimetabolites and hormones, cause a sharp decline in the antioxidant activity (AOA) of liver lipids after administration. The decline is directly proportional to the administered dose. In other words, chemotherapy, like radiotherapy, is a powerful initiator of lipid peroxidation (LPO) in patients undergoing these procedures (V.I. Pakhomov, 2001). Administering exogenous antioxidants such as vitamin E to increase AOA does not produce positive results. In the experiment, animals receiving these substances died sooner than controls because exogenous antioxidants blocked their endogenous antioxidant system, causing antioxidant defence to fail (E.B.
Burlakova, 1975).
The relatively high incidence of chemotherapy complications is primarily associated with imbalance between LPO and AOA (V.I. Pakhomov, 1995); chemotherapy damages healthy tissues to a much greater extent than the tumour itself (V.I. Pakhomov, 2001). Complex processes within the tumour at different stages of development, including simultaneous proliferation and destruction in different areas, activate both LPO and AOA. Researchers therefore face the difficult task of finding treatments or drugs capable of normalising both processes simultaneously.
Normobaric hypoxic exposure is one promising approach to reducing chemotherapy complications (R.B. Strelkov et al., 1975–2001). By increasing nonspecific resistance, it stabilises LPO–AOA processes (V.A. Maslov, 2003).
Interest in free-radical processes in cancer, particularly during chemotherapy, remains high (E.W. Jensen, 1950; F. Gordy, 1960; E.A. Neifakh, 1963; S.L. Daryalova, 1983; V.I. Pakhomov, 1995, 2001). Some authors, including A.Kh. Kogan (1983) and V.I. Pakhomov (2001), believe stabilising the LPO–AOA system will help address several oncological problems, including chemotherapy complications.
We therefore investigated the influence of intermittent normobaric hypoxia (INH) on the LPO–AOA system during chemotherapy. Exhaled pentane was measured because, alongside ethane, it is a reliable indicator of LPO–AOA intensity (V.N. Shilov and V.I. Sergienko, 1998; V.F. Fokin and N.V. Ponomareva, 2001; V.A. Maslov et al., 2003; R. Undas, 1975; E.W. Jenson, 1950; F.L. Rodkey, 1974). Pentane is a breakdown product of lipid hydroperoxides (G.D. Cohen et al., 1982; G.A.A. Kivits, 1981).
Methodology
Pentane concentration was determined by gas chromatography.
Specialists from the gas-chromatography methods laboratory at the I.V. Kurchatov Institute of Atomic Energy, Moscow, used a Crom-5 gas chromatograph (Czech Republic). The same laboratory engineer performed every analysis. Samples were collected before and 20–25 minutes after each INH session. Results underwent automated computer processing.
Thirty-three patients diagnosed with disseminated breast cancer following surgery were examined using a blinded method and divided into three groups.
In group 1, 12 patients began INH with the first cytostatic administration. In group 2, 11 began INH eight days before chemotherapy. The ten controls received no INH. Ages were 47.4±3.8, 52.4±5.1 and 51.3±4.3 years in groups 1, 2 and 3, respectively.
All three groups received identical chemotherapy and detoxification regimens. A two-week chemotherapy course was followed by a three-week break. It comprised cyclophosphamide 400 mg intramuscularly every other day to a total of 2.8 g; methotrexate 30 mg/m² on days 1 and 8; and 5-fluorouracil 500 mg/m² on days 1 and 8. Hemodez, rheopolyglucin, 5% glucose solution and ascorbic acid were also given. Daily fluid administration was up to 2.5 litres.
INH was delivered using a hypoxicator according to the method developed by R.B. Strelkov and colleagues (1975–2001).
Group 1 received two INH sessions daily: before the chemotherapy drug and 20–25 minutes after administration. This schedule continued for 14 days, whether or not chemotherapy was administered that day. Exhaled pentane and clinical condition were assessed daily at the same time.
Group 2 began twice-daily INH seven or eight days before chemotherapy. Sessions then continued for 14 treatment days, both on chemotherapy days and on other days. As in group 1, exhaled pentane and clinical condition were assessed daily at the same time.
Controls received no INH. Only exhaled pentane after drug administration was monitored using the method described above, alongside assessment of the patient’s condition.
Results were processed using Student’s and Fisher’s variation-statistical methods. The arithmetic mean and its standard error (M±m), and the significance of differences between means (P), were calculated. Results with P≤0.05 were considered significant.
Results and discussion
Figure 1 shows exhaled pentane in group 1, in which INH began with chemotherapy. Treatment days are plotted on the horizontal axis and pentane concentration in ppm on the vertical axis.
The graph shows exhaled pentane before and throughout chemotherapy combined with INH. On chemotherapy day 1, pentane rose from 2.18±0.08 ppm before treatment to 3.56±0.06 ppm (P<0.01). With INH, it then fell from 3.56±0.06 ppm on day 1 to 2.04±0.09 ppm on day 7 (P<0.01). Repeat chemotherapy on day 8 produced an expected rise to 3.26±0.1 ppm (P<0.01), still below the first chemotherapy day’s value. From day 9 to day 14, exhaled pentane declined to 1.47±0.04 ppm (P<0.01). This indicates reduced free-radical activity and activation of the antioxidant system, ultimately stabilising cell biomembranes. Lower pentane is also a favourable sign of reduced chemotherapy toxicity to metabolic processes.
Patients simultaneously improved clinically: sleep normalised and vomiting was replaced by mild nausea. Appetite remained fully preserved and well-being during chemotherapy was considered relatively satisfactory. Patients spent considerable time walking.
Hypoxic therapy before chemotherapy
Figure 2 shows exhaled pentane in group 2, which began INH seven or eight days before chemotherapy and continued it during the following 14 treatment days. Baseline pentane was 2.12±0.06 ppm, virtually matching group 1’s 2.18±0.08 ppm (P<0.05).
This graph has two parts: INH without chemotherapy, followed by INH during chemotherapy. In the first part, LPO declined from the first to the eighth INH session, with pentane falling from 2.12±0.06 to 0.86±0.04 ppm (P<0.05). The findings indicate reduced free-radical activity through endogenous antioxidant production and stronger antioxidant defence.
After the first cytostatic administration, free-radical activity nearly doubled to 1.5±0.06 ppm (P<0.02), but unlike group 1 it did not exceed baseline.
A clear downward trend in free-radical activity followed. Exhaled pentane fell to 0.64±0.03 ppm by the seventh INH session (P<0.05). On treatment day 8, when methotrexate and 5-fluorouracil were repeated, it rose to 0.98±0.026 ppm (P<0.01). This rise was far smaller than in group 1. We believe this reflects the preventive INH course before chemotherapy. The fall in exhaled pentane corresponded to clinical improvements: throughout treatment, patients had no nausea and maintained normal sleep and appetite. They subjectively rated their condition as good, with no physical-activity restrictions.
Control group
Figure 3 shows pentane changes in controls, who received no INH.
The graph presents LPO changes in controls without INH. Baseline pentane was 2.08±0.06 ppm, comparable with groups 1 and 2. Starting chemotherapy sharply activated free-radical processes: pentane rose from 2.08±0.06 to 4.75±0.12 ppm (P<0.01). Continued chemotherapy increased free-radical activity still further. By day 8, with repeat methotrexate and 5-fluorouracil, it reached 6.72±0.23 ppm. These findings indicate substantial chemotherapy-induced lipid peroxidation, accompanied by exhausted adaptive mechanisms, destabilised metabolism and suppressed endogenous antioxidant production.
Conclusions
The results support the following conclusions:
1. Gas chromatography is a highly accurate and informative method for studying free-radical processes. It can monitor changes in the LPO–AOA system during chemotherapy.
2. Chemotherapy activates free-radical oxidation, particularly lipid peroxidation in cell biomembranes.
3. INH during chemotherapy suppresses lipid peroxidation by stimulating endogenous antioxidant production, ultimately stabilising cell membranes. Clinically, this is accompanied by fewer chemotherapy complications.
4. Preventive INH before planned chemotherapy reduces free-radical activity in advance, stabilises biomembranes, increases AOA and restores adaptive regulatory mechanisms, thereby preparing the patient for chemotherapy.
5. Preventive INH reduces LPO during chemotherapy more than starting INH at the same time as chemotherapy. This is accompanied by both greater AOA activation during treatment and more pronounced favourable clinical results, expressed as fewer chemotherapy complications.
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Full main-text translation of: Маслов В.А., Бесова Н.С., Лапшин В.П. Влияние нормобарической гипокситерапии на перекисное окисление липидов при проведении химиотерапии онкологическим больным. Клиническая больница № 6 Федерального управления «Медбиоэкстрем» при Минздраве РФ, Москва. С. 52–61.
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