Usefulness of Honey as an Adjunct in the Radiation Treatment for Head and Neck Cancer: Emphasis on Pharmacological and Mechanism/s of Actions.

BACKGROUND: In the treatment of head and neck cancer (HNC), ionizing radiation is an important modality in achieving curative objectives. However, the effective use of radiation is compromised by the side effects resulting from the damage to the adjacent normal tissue. Preclinical studies carried out in the recent past have shown that the age-old dietary agent honey, which also possesses myriad medicinal use, is beneficial for mitigating diverse radiation-induced side effects like mucositis, xerostomia, fatigue, weight loss and promoting healing of refractory wounds. OBJECTIVE: The objective of this memoir is to review the beneficial effects of honey in mitigating radiation-induced side effects in HNC and to emphasize on the underlying mechanisms of action for inducing the beneficial effects. METHODS: Two authors searched Google Scholar, PubMed, Embase, and the Cochrane Library for publications up to December 2019 to assess the capability of honey for reducing the severity of radiation-induced ill effects in the treatment of HNC. Subsequently, the adjunct pharmacological effects and mechanism/s responsible were also searched for and appropriately used to substantiate the underlying mechanism/s of action for the beneficial effects. RESULTS: The existing data is suggestive that honey is beneficial in mitigating the radiation-induced mucositis, xerostomia, amd healing of recalcitrant wounds in radiation-exposed regions, and that the multiple pathways mediate the beneficial effects, especially free radical scavenging, antioxidant, wound healing, anticancer, analgesic, anti-inflammatory, anabolic, anti-fatigue and anti-anaemic effects that add additional value to the use of honey as an adjunct in cancer therapy. CONCLUSION: For the first time, this review addresses the underlying pharmacological related to the beneficial effects of honey in radiation-induced damage, and attempts at emphasizing the lacunae that need further studies for optimizing the use of honey as an adjunct in radiotherapy of HNC. The authors suggest that future studies should be directed at understanding the detailed molecular mechanisms responsible for the beneficial effects using validated cell culture and animal models of study. Large multicentric clinical trials with standardised honey also needed to understand the clinical use of honey.

Indian Indigenous Fruits as Radioprotective Agents: Past, Present and Future.

Ionising radiation has been an important modality in cancer treatment and its value is immense when surgical intervention is risky or might debilitate/adversely affect the patient. However, the beneficial effect of radiation modality is negated by the damage to the adjacent healthy tissue in the field of radiation. Under these situations, the use of radioprotective compounds that can selectively protect normal tissues against radiation injury is considered very useful. However, research spanning over half a century has shown that there are no ideal radioprotectors available. The United States Food and Drug Administration (FDA or USFDA) approved amifostine, or WR-2721 (Walter Reed-2721) [chemically S-2-(3-aminopropyl-amino) ethyl phosphorothioic acid] is toxic at their optimal concentrations. This has necessitated the need for agents that are safe and easily acceptable to humans. BACKGROUND: Dietary agents with beneficial effects like free radical scavenging, antioxidant and immunomodulatory effects are being recognized as useful and have been investigated for their radioprotective properties. Studies in these lines have shown that the fruits of Aegle marmelos (stone apple or bael), Emblica officinalis or Phyllanthus emblica (Indian gooseberry/amla), Eugenia jambolana or Syzygium jambolana (black plum/jamun), Mangifera indica (mango) and Grewia asiatica (phalsa or falsa) that are originally reported to be indigenous to India have been investigated for their usefulness as radioprotective agents. OBJECTIVE: The objective of this review is to summarize the beneficial effects of the Indian indigenous fruits, stone apple, mango, Indian gooseberry, black plum, and phalsa, in mitigating radiation-induced side effects, emphasize the underlying mechanism of action for the beneficial effects and address aspects that merit detail investigations for these fruits to move towards clinical application in the near future. METHODS: The authors data-mined Google Scholar, PubMed, Embase, and the Cochrane Library for publications in the field from 1981 up to July 2020. The focus was on the radioprotection and the mechanism responsible for the beneficial effects, and accordingly, the articles were collated and analyzed. RESULTS: This article emphasizes the usefulness of stone apple, mango, Indian gooseberry, black plum, and phalsa as radioprotective agents. From a mechanistic view, reports are suggestive that the beneficial effects are mediated by triggering free radical scavenging, antioxidant, anti-mutagenic and anti-inflammatory effects. CONCLUSION: For the first time, this review addresses the beneficial effects of mango, Indian gooseberry, black plum, stone apple and phalsa as radioprotective agents. The authors suggest that future studies should be directed at understanding the selective radioprotective effects with tumor-bearing laboratory animals to understand their usefulness as radioprotective drug/s during radiotherapy and as a food supplement to protect people from getting exposed to low doses of radiation in occupational settings. Phase I clinical trial studies are also required to ascertain the optimal dose and the schedule to be followed with the standardized extract of these fruits. The most important aspect is that these fruits, being a part of the diet, have been consumed since the beginning of mankind, are non-toxic, possess diverse medicinal properties, have easy acceptability, all of which will help take research forward and be of benefit to patients, occupational workers, agro-based sectors and pharma industries.

Modulation of doxorubicin-induced genotoxicity by Aegle marmelos in mouse bone marrow: a micronucleus study.

The effect of various concentrations of Aegle marmelos (AME) on the doxorubicin (DOX)-induced genotoxic effects in mice bone marrow was studied. Treatment of mice with different concentrations of DOX resulted in a dose-dependent elevation in the frequency of micronucleated polychromatic (MPCE) as well as normochromatic (MNCE) erythrocytes in mouse bone marrow. The frequencies of MPCE and MNCE increased with scoring time, and the greatest elevation for MPCE was observed at 48 hours post-DOX treatment, whereas a maximum increase in MNCE was observed at 72 hours post-DOX treatment. This increase in MPCE and MNCE was accompanied by a decline in the polychromatic erythrocytes-normochromatic erythrocytes (PCE/NCE) ratio, which showed a DOX-dose-dependent decline. Treatment of mice with 200, 250, 300, 350, and 400 mg/kg body weight of AME, orally once daily for 5 consecutive days before DOX treatment, significantly reduced the frequency of DOX-induced micronuclei accompanied by a significant elevation in the PCE/NCE ratio at all scoring times. The greatest protection against DOX-induced genotoxicity was observed at 350 mg/kg AME. The protection against DOX-induced genotoxicity by AME may be due to inhibition of free radicals and increased antioxidant status.

Evaluation of the radioprotective effect of Liv 52 in mice.

Liv 52 is a mixture of botanicals that is used clinically to treat various hepatic disorders. In this study, the radioprotective activity of Liv 52 was evaluated in mice given whole-body exposure to different doses of gamma-radiation. In addition, a series of studies was conducted to explore the mechanism of radioprotection. Radioprotection was evaluated by the ability of Liv 52 to reduce both the frequency of bone marrow micronucleated erythrocytes and the lethality produced by (60)Co gamma-radiation. Mice were treated by oral gavage once daily for seven consecutive days with 500 mg/kg body weight Liv 52 or carboxymethylcellulose vehicle prior to radiation. Micronucleated polychromatic erythrocytes (MPCEs), micronucleated normochromatic erythrocytes (MNCEs), and the PCE/NCE ratio were measured at 0.25-14 days after exposure to whole-body radiation doses of 0, 0.5, 1.5, 3.0, or 4.5 Gy; animal survival was monitored after doses of 7, 8, 9, 10, 11, or 12 Gy. Pretreatment of mice with Liv 52 significantly reduced the frequency of radiation-induced MPCEs and MNCEs. Irradiation reduced the PCE/NCE ratio in a dose-related manner for up to 7 days following irradiation; Liv 52 pretreatment significantly mitigated against these reductions. Liv 52 treatment also reduced the symptoms of radiation sickness and increased mouse survival 10 and 30 days after irradiation. Liv 52 pretreatment elevated the levels of reduced glutathione (GSH), increased the activities of glutathione transferase, GSH peroxidase, GSH reductase, superoxide dismutase, and catalase, and lowered lipid peroxidation (LPx) and the activities of alanine amino transferase and aspartate aminotransferase 30 min after exposure to 7 Gy of gamma-radiation. Liv 52 pretreatment also reduced radiation-induced LPx and increased GSH concentration 31 days following the exposure. The results of this study indicate that pretreatment with Liv 52 reduces the genotoxic and lethal effects of gamma-irradiation in mice and suggest that this radioprotection may be afforded by reducing the toxic effects of the oxidative products of irradiation.

Effects of Aegle marmelos (L.) Correa on the peripheral blood and small intestine of mice exposed to gamma radiation.

The radioprotective effect of bael (Aegle marmelos, AME) extract was studied in Swiss albino mice against radiation-induced changes in the peripheral blood, spleen colony forming units, and intestinal mucosa. The mice were treated with 250 mg/kg body weight of AME orally once daily for five consecutive days before exposure to an acute dose of 7 Gy of gamma radiation after the last administration. The peripheral blood was collected and evaluated for red blood cell (RBC), hemoglobin, total leukocyte count (TLC), and lymphocyte count on days one and seven postirradiation. The nucleated bone marrow cells were isolated and tested for colony-forming units (CFUs) in spleen at days one and seven. AME protected mice against the radiation-induced decline in hemoglobin, total leukocyte, and lymphocytes counts and the clonogenicity of hemopoietic progenitor cells assessed by the exogenous spleen colony-forming assay. Irradiation of mice caused a significant decline in the villus height and crypt number with an increase in goblet and dead cells in the small intestine, where the maximum changes were observed on day one postirradiation, indicating a severe damage, and signs of recovery at day seven postirradiation. Treatment of mice with AME before irradiation elevated the peripheral cell count as well as villus height and the crypt number accompanied by a decline in goblet and dead cells when compared with the irradiation control. The recovery and regeneration were faster in AME pretreated animals than the irradiation alone. AME pretreatment significantly decreased lipid peroxidation accompanied by a significant elevation in the GSH concentration in the mouse intestine. The data clearly indicate that the AME significantly reduced the deleterious effect of radiation in the intestine and bone marrow of mouse and could be a useful agent in reducing the side effects of therapeutic radiation.

Radioprotection by oral administration of Aegle marmelos (L.) Correa in vivo.

The radioprotective effect of an extract of Aegle marmelos (L.) Correa (AME), family Rutaceae, was investigated in mice exposed to different doses of gamma-radiation. Mice were administered orally AME 250 mg/kg b.wt. orally daily for 5 consecutive days before exposure to 6, 7, 8, 9, 10, or 11 Gy of gamma-radiation. The animals were monitored daily up to 30 days after irradiation for the development of symptoms of radiation sickness or death. Treatment of mice with AME before irradiation reduced the symptoms of radiation sickness and delayed death compared to the irradiated controls given sterile physiological saline (SPS). AME provided protection against both gastrointestinal and hematopoietic toxicities. Reducing the administration schedule of AME to 1 or 3 consecutive days or increasing the schedule to 7 consecutive days was not as effective as 5 consecutive days of preradiation schedule. The administration of AME after irradiation was not effective, and no survivors could be reported 30 days after irradiation. The LD50/30 was found to be 8.1 Gy for the SPS + irradiation group and 9.7 Gy for the AME + irradiation group. The oral administration of AME resulted in an increase in radiation tolerance by 1.6 Gy, and the dose reduction factor was found to be 1.2. Preradiation treatment of mice with AME caused a significant depletion in lipid peroxidation followed by a significant elevation in glutathione concentration in the liver of mice 31 days after irradiation. The drug was nontoxic up to a dose of 6000 mg/kg b.wt., the highest drug dose that could be tested for acute toxicity.

Influence of seed extract of Syzygium Cumini (Jamun) on mice exposed to different doses of gamma-radiation.

The radioprotective activity of the hydroalcoholic extract of jamun seeds (SCE) was studied in mice exposed to different doses of gamma radiation. The mice were injected with 0, 5, 10, 20, 40, 60, 80, 100, 120, 140 or 160 mg/kg body weight of SCE, before exposure to 10 Gy of gamma radiation, to select the optimum dose of radiation protection. The 80 mg/kg SCE was found to offer highest protection, therefore, further studies were carried out using this dose. The drug was more effective when administered through the intraperitoneal route at equimolar doses than the oral route. Since higher survival was observed for the i.p. route (50%), than the oral route (29.2%), all other studies were carried out by injecting SCE intraperitoneally. The mice treated with 80 mg/kg body weight SCE intraperitoneally before exposure to 6, 7, 8, 9, 10 and 11 Gy of gamma radiation showed reduction in the symptoms of radiation sickness and mortality at all exposure doses and caused a significant increase in the animal survival when compared with the concurrent double distilled water (DDW) + irradiation group. The SCE treatment protected mice against the gastrointestinal as well as bone marrow deaths and the DRF was found to be 1.24.

Evaluation of the cytotoxic effect of the monoterpene indole alkaloid echitamine in-vitro and in tumour-bearing mice.

The cytotoxic effect of various concentrations of echitamine chloride was studied in HeLa, HepG2, HL60, KB and MCF-7 cell lines in-vitro and in mice bearing Ehrlich ascites carcinoma (EAC). Exposure of various cells to different concentrations of echitamine chloride resulted in a concentration-dependent cell killing, and KB cells were found to be most sensitive amongst all the cells evaluated. EAC mice treated with 1, 2, 4, 6, 8, 12 or 16 mg kg-1 echitamine chloride showed a dose-dependent elevation in the anti-tumour activity, as evident by increased number of survivors in comparison with the non-drug treated controls. The highest dose of echitamine chloride (16 mg kg-1) caused toxicity in the recipient mice, therefore 12 mg kg-1 was considered the best cytotoxic dose for its anti-tumour effect. Administration of 12 mg kg-1 echitamine chloride resulted in an increase in the median survival time (MST) up to 30.5 days, which was 11.5 days higher than the non-drug treated control (19 days). Administration of 16 mg kg-1 echitamine chloride to EAC mice resulted in a time dependent elevation in lipid peroxidation that reached a peak at 6 h post-treatment, whereas glutathione concentration declined in a time dependent manner and a maximum decline was reported at 3 h post-treatment. Our study demonstrated that echitamine chloride possessed anti-tumour activity in-vitro and in-vivo.

Influence of ginger rhizome (Zingiber officinale Rosc) on survival, glutathione and lipid peroxidation in mice after whole-body exposure to gamma radiation.

The radioprotective effect of the hydroalcoholic extract of ginger rhizome, Zingiber officinale (ZOE), was studied. Mice were given 10 mg/kg ZOE intraperitoneally once daily for five consecutive days before exposure to 6-12 Gy of gamma radiation and were monitored daily up to 30 days postirradiation for the development of symptoms of radiation sickness and mortality. Pretreatment of mice with ZOE reduced the severity of radiation sickness and the mortality at all doses. The ZOE treatment protected mice from GI syndrome as well as bone marrow syndrome. The dose reduction factor for ZOE was found to be 1.15. The optimum protective dose of 10 mg/kg ZOE was 1/50 of the LD50 (500 mg/kg). Irradiation of the animals resulted in a dose-dependent elevation in the lipid peroxidation and depletion of GSH on day 31 postirradiation; both effects were lessened by pretreatment with ZOE. ZOE also had a dose-dependent antimicrobial activity against Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli and Candida albicans.

Effect of Sapthaparna (Alstonia scholaris Linn) in modulating the benzo(a)pyrene-induced forestomach carcinogenesis in mice.

The chemopreventive effect of various doses of hydroalcoholic extract of Alstonia scholaris (ASE) was studied on the benzo(a)pyrene (BaP) induced forestomach carcinoma in female mice. The treatment of mice with different doses, i.e. 1, 2 and 4 mg/ml ASE in drinking water before, during and after the treatment with carcinogen, exhibited chemopreventive activity. The highest activity was observed for 4 mg/ml ASE, where the tumor incidence (93.33%) was reduced by 6.67%. Similarly, the tumor multiplicity reduced (61.29%) significantly (P<0.02) at 4 mg/ml in the pre-post-ASE treated group. However, the pre or post-treatment of mice with 4 mg/ml ASE did not show chemopreventive activity. These findings are corroborated by micronucleus assay, where treatment of mice with ASE before, during and after carcinogen treatment reduced the frequency of micronuclei (MN) in the splenocytes in a dose dependent manner. The MN frequency reached a nadir at 4 mg/ml ASE, the highest drug dose which showed maximum chemopreventive action. The ASE treatment not only reduced the frequency of splenocytes bearing one MN but also cells bearing multiple MN indicating the efficacy of ASE in inhibiting mutagenic changes induced by BaP. The pre or post-treatment of mice with 4 mg/ml ASE also significantly reduced the frequency of BaP-induced MN in the splenocytes of treated animals.

The evaluation of the acute toxicity and long term safety of hydroalcoholic extract of Sapthaparna (Alstonia scholaris) in mice and rats.

The acute and sub-acute toxic effects of various doses of hydroalcoholic extract of Alstonia scholaris (ASE) was studied in mice and rats. The acute toxicity in mice depended on the season of collection of plant. The highest acute toxicity was observed in the ASE prepared from the summer collection followed by winter. The least toxicity was observed in the extract prepared from the bark of A. scholaris collected in the monsoon season. The administration of different doses of ASE showed a dose dependent increase in the toxicity in all species of mice. The Swiss albino mice were found to be the most sensitive followed by the DBA and C(57)BL. The crossbred mice were resistant when compared to the pure inbred strains. The oral administration of ASE was non-toxic up to a dose of 2000 mg/kg b. wt., while maximum number of animals succumbed to death after administration of 1100 mg/kg ASE by intraperitoneal route. The rats were more sensitive than the mice as the LD(50) dose of ASE was lesser for the former than the latter. The sub-acute toxicity in the rats was carried out with 120 and 240 mg/kg b. wt. ASE (1/10th and 1/5th of the LD(50) dose of ASE). The 240 mg was observed to be more toxic than 120 mg/kg ASE since it caused mortality and deformity in various organs of the recipient animals. The various biochemical parameters like AST, ALT, ACP, ALP, CK, LDH, creatinine, urea, ammonia, glucose and LPx were higher at 240 mg/kg ASE when compared with the 120 mg and the non-drug treated animals. In contrast, the total protein, albumin, DNA, RNA, cholesterol, glucose, glutathione, total thiols declined in the 240 mg/kg ASE treated animals when compared with non-drug treated controls. The hematological analysis showed a dose dependent decrease in the RBC, WBC, hemoglobin, neutrophils and monocytes, while a significant increase in the lymphocytes, eosinophils and basophils was observed. The observed toxic effect of ASE may be due to the presence of echitamine. Our studies shows that at high doses, A. scholaris exhibited marked damage to all the major organs of the body.

Fruit extract of Aegle marmelos protects mice against radiation-induced lethality.

The radioprotective effect of a hydroalcoholic extracted material from the fruit of Aegle marmelos (AME) was studied in mice exposed to different doses of gamma radiation. The optimum dose for radioprotection was determined by administering 0, 5, 10, 20, 40, or 80 mg/kg body weight of AME intraperitoneally (ip) once daily, consecutively for 5 days before exposure to 10 Gy of gamma radiation. A total of 20 mg/kg of AME for 5 consecutive days before irradiation was found to afford maximum protection as evidenced by the highest number of survivors after 30 days postirradiation. Animals from all groups were monitored for 30 days postirradiation for development of symptoms of radiation sickness and mortality. Treatment of mice with AME before exposure to different doses of gamma radiation reduced the severity of symptoms of radiation sickness and mortality with all exposure doses. This was accompanied by an increase in number of survivors in the AME + irradiation group when compared with the concurrent sterile physiological saline (SPS) + irradiation group. AME pretreatment protected mice against the gastrointestinal as well as bone marrow deaths, as evidenced by the greater number of survivors on day 10 or 30, respectively. LD50/30 was found to be 8.2 Gy for the SPS + irradiation group, while it was 8.8 Gy for AME + irradiation. The dose-reduction factor (DRF) was found to be 1.1 for AME + irradiation group. The acute toxicity study of AME showed that it was nontoxic up to a dose of 6 g/kg body weight, the highest drug dose that could be administered. Irradiation of animals resulted in a dose-dependent elevation in lipid peroxidation in liver, kidney, stomach, and intestine of mice. Conversely, GSH concentration declined in a dose-dependent manner. Treatment of animals with AME before irradiation caused a significant decrease in the lipid peroxidation accompanied by a significant elevation in the GSH concentration in liver, kidney, stomach, and intestine of mice determined at 31 days postirradiation.

Ginger (Zingiber officinale Rosc.), a dietary supplement, protects mice against radiation-induced lethality: mechanism of action.

The radioprotective effect of hydroalcoholic extract of ginger rhizome (Zingiber officinale; ZOE) was studied in mice administered 250 mg/kg ZOE orally using oral gavage once daily for 5 consecutive days before exposure to 6, 7, 8, 9, 10, or 11 Gy of gamma-radiation. The animals were monitored daily up to 30 days postirradiation for the development of symptoms of radiation sickness and mortality. Pretreatment of mice with ZOE reduced the severity of symptoms of radiation sickness and mortality at all the exposure doses and also increased the number of survivors in a ZOE + irradiation group compared to the concurrent double-distilled water + irradiation group. The ZOE treatment protected mice against gastrointestinal-related deaths as well as bone-marrow-related deaths. The dose-reduction factor was found to be 1.2. The administration of ZOE after exposure to irradiation was not effective, as no survivors lasted up to 30 days postirradiation. Reducing the administration schedule to 3 days or increasing the schedule to 7 days was not as effective compared to a 5 consecutive days' schedule. The irradiation of animals resulted in a dose-dependent elevation in the lipid peroxidation, while depletion in the glutathione (GSH) contents occurred on day 31 postirradiation. Treatment of mice with ZOE before irradiation caused a significant depletion in lipid peroxidation followed by a significant elevation in GSH concentration in the livers of mice at 31 days postirradiation. The mechanism of action of ZOE was determined by evaluating its free-radical scavenging capability. Ginger was found to scavenge *OH, O2*- and ABTS*+ radicals in a dose-dependent manner in vitro. The drug was nontoxic up to a dose of 1500 mg/kg body weight, the highest drug dose that could be tested for acute toxicity.

Triphala, an ayurvedic rasayana drug, protects mice against radiation-induced lethality by free-radical scavenging.

The effects of 10 mg/kg of triphala extract (TE) was studied on radiation-induced sickness and mortality in mice exposed to 7-12 Gray (Gy) of gamma-irradiation. Treatment of mice with triphala once daily for 5 consecutive days before irradiation delayed the onset of mortality and reduced the symptoms of radiation sickness when compared with the non-drug double distilled water treated irradiated controls (DDW). Triphala provided protection against both gastrointestinal and hemopoetic death. However, animals of both the TE + irradiation and DDW + irradiation groups did not survive up to 30 days post-irradiation beyond 11 Gy irradiation. The LD50/30 was found to be 8.6 Gy for the DDW + irradiation group and 9.9 Gy for TE + irradiation group. The administration of triphala resulted in an increase in the radiation tolerance by 1.4 Gy, and the dose reduction factor was found to be 1.15. To understand the mechanism of action of triphala, the free radical scavenging activity of the drug was evaluated. Triphala was found to scavenge (.)OH, O(2) (.) 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonate) diammonium salt (ABTS)(.+) and NO(.) radicals in a dose dependent manner.

Aegle marmelos (L.) Correa (Bael) and its phytochemicals in the treatment and prevention of cancer.

Aegle marmelos, commonly known as Bael and belonging to the family Rutaceae is an important medicinal plant in the traditional Indian system of medicine, the Ayurveda. The extract prepared by boiling the bark, leaves or roots in water is useful as laxative, febrifuge, and expectorant. The extract is also useful in ophthalmia, deafness, inflammations, catarrh, diabetes, and asthmatic complaints. The fruits are used in treating diarrhea, dysentery, stomach ache, and cardiac ailments. Scientific studies have validated many of Bael's ethnomedicinal properties and its potential antimicrobial effects, hypoglycemic, astringent, antidiarrheal, antidysenteric, demulcent, analgesic, anti-inflammatory, antipyretic, wound-healing, insecticidal, and gastroprotective properties. In addition, studies have also shown that Bael and some of the Bael phytochemicals possess antineoplastic, radioprotective, chemoprotective, and chemopreventive effects, properties efficacious in the treatment and prevention of cancer. For the first time, the current review summarizes the results related to these properties and emphasizes aspects that require further investigation for Bael's safe and effective use in the near future.

Radioprotective effects of Aegle marmelos (L.) Correa (Bael): a concise review.

The effective use of radiotherapy in cancer cure and palliation is compromised by the side-effects resulting from radiosensitivity of bordering normal tissues, which are invariably exposed to the cytotoxic effects of ionizing radiation during treatment. In this situation, use of radioprotective compounds that can protect normal tissues against radiation injury are of immense use. In addition to protecting normal tissue these compounds will also permit use of higher radiation doses to obtain better cancer control and possible cure. However, to date, no ideal radioprotectors are available as most synthetic compounds are toxic at their optimal concentrations and have produced little success in clinics. Radiation ill-effects are principally the result of generation of free radicals, and the antioxidant compounds that counter them are supposed to be of immense use in preventing them. In Ayurveda, the traditional Indian system of medicine, several plants have been observed to avert/ameliorate free radical-mediated ailments--an effect that has been documented--and such plants have recently been the focus of attention. Aegle marmelos (L.) Correa (Bael), commonly known as bael, has been used since antiquity for treating various ailments, some of which are now known to be the result of oxidative stress. In studies spanning nearly a decade, it has been observed that bael prevented radiation-induced ill-effects, and the results of these studies indicate that it has the potential to be an effective, nontoxic radioprotective agent. In this current review, for the first time, an attempt is made to summarize these observations and to discuss the plausible reasons responsible for bael's radioprotective effects.

REMOVED: Inhibition of doxorubicin-induced clastogenic effect by Aegle marmelos (L.) correa in cultured V79 cells.

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Aegle marmelos (L.) Correa inhibits the proliferation of transplanted Ehrlich ascites carcinoma in mice.

The anticancer effect of hydroalcoholic extract of Aegle marmelos (AME) was studied in the Ehrlich ascites carcinoma bearing Swiss albino mice. The spatial effect of various AME administration schedules showed that six-day administration increased the survival of tumor bearing mice. The best antineoplastic action of AME was obtained when AME administered through intraperitoneal route than the oral route at equimolar dose. Administration of AME once daily for six consecutive days to the tumor bearing mice caused a dose dependent remission of the tumor at 400 mg/kg body weight, where the greatest antitumor effect was observed and the higher doses showed toxic manifestations. A 24-d lengthening in life span was observed in EAC animals treated with 400 mg/kg AME. This dose of 400 mg/kg was considered as the best dose, where the animals survived up to 43 d post-tumor-cell inoculation as against no survivors in the saline treated control group. The antitumor activity when tested for different schedules for triple administrations, the best effect was observed for 1-2-3, followed by 1-3-5 and 1-5-9 days, respectively. Stage specific evaluation of AME inhibited the increase in body weight gain in animals due to tumor development during early stages only. The AME treatment resulted in a dose dependent elevation in the median survival time (MST) and average survival time (AST) up to 400 mg/kg AME and decline thereafter. The effective dose of 400 mg of AME is 1/6th of the LD50 dose, which increased the MST and AST up to 29 and 27 d, respectively. The acute toxicity study of AME showed that the drug was non-toxic up to a dose of 1750 mg/kg b. wt. The LD10 and LD50 was found to be 2000 and 2250 mg/kg.

Evaluation of the radioprotective effect of Aegle marmelos (L.) Correa in cultured human peripheral blood lymphocytes exposed to different doses of gamma-radiation: a micronucleus study.

The radioprotective effect of a hydroalcoholic extract of Aegle marmelos (AME) was evaluated in cultured human peripheral blood lymphocytes (HPBLs) by the micronucleus assay. The optimum protective dose of the extract was selected by treating HPBLs with 1.25, 2.5, 5, 6.25, 10, 20, 40, 60, 80 and 100 microg/ml AME before exposure to 3 Gy gamma-radiation and then evaluating the micronucleus frequency in cytokinesis blocked HPBLs. Treatment of HPBLs with different doses of AME reduced the frequency of radiation-induced micronuclei significantly, with the greatest reduction in micronucleus induction being observed for 5 microg/ml AME. Therefore, this dose of AME was considered as the optimum dose for radioprotection and further studies were carried out treating the HPBLs with 5 microg/ml AME before exposure to different doses (0, 0.5, 1, 2, 3 and 4 Gy) of gamma-radiation. The irradiation of HPBLs with different doses of gamma-radiation caused a dose-dependent increase in the frequency of lymphocytes bearing one, two and multiple micronuclei, while treatment of HPBLs with 5 microg/ml AME significantly reduced the frequency of lymphocytes bearing one, two and multiple micronuclei when compared with the irradiated control. The dose-response relationship for both groups was linear. To understand the mechanism of action of AME separate experiments were conducted to evaluate the free radical scavenging of OH, O2(-), DPPH, ABTS(+) and NO in vitro. AME was found to inhibit free radicals in a dose-dependent manner up to a dose of 200 microg/ml for the majority of radicals and plateaued thereafter. Our study demonstrates that AME at 5 microg/ml protected HPBLs against radiation-induced DNA damage and genomic instability and its radioprotective activity may be by scavenging of radiation-induced free radicals and increased oxidant status.