Effect of carbogen on tumour oxygenation and 32P-colloid interstitial irradiation response.

BACKGROUND: Interstitial irradiation therapy using radionuclides is a slow and continual process in which the effect is exerted gradually, thus improvement of the hypoxic status of the tumor will also take a long time. It has been known that carbogen delivery of 5-15 min increases tumor oxygenation. However, the long-term effect of carbogen breathing on hypoxic cells has not yet been determined, and little is know about the effect of carbogen breathing for sensitization to interstitial irradiation therapy. MATERIAL/METHODS: 99mTc-HL91(99mTc 4,9-diaza-3,3,10,10-tetramethyldodecan-2,1-dione dioxime) hypoxic imaging was performed in 10 mice bearing sarcoma 180 (S180) before and after 2 h carbogen breathing. Radioactivity ratios of tumor to contralateral limbs (T/L) of the 2 images were calculated and compared. Mice bearing S180 were subjected to long-term carbogen breathing (2 h/day for 24 days), and were treated with or without 32P-colloid. Tumor growth rate was observed in the S180-bearing mice. RESULTS: T/L of 99mTc-HL91 uptake before and after carbogen breathing was 1.872+/-0.391 and 1.354+/-0.189, respectively (t=4.476, P<0.01). In mice in the 32P-treated air breathing group and 32P-treated carbogen breathing group, tumor growth rate did not differ on day 12 after 32P-colloid treatment, and on day 24 the tumor volume was 2.728+/-0.469 and 2.237+/-0.603 cm3 (t=2.128, P<0.05), respectively, with tumor mass being 2.437+/-0.447 and 1.965+/-0.538 g (t=2.134, P<0.05), respectively. CONCLUSIONS: Long-term carbogen breathing can increase tumor oxygenation and continual carbogen breathing is necessary for enhancing the therapeutic effect of 32P-colloid interstitial irradiation.

The effect of dead cells on the activity of actinomycin D against mouse sarcoma 180 ascites.

It has been demonstrated that cells killed by heat or irradiation have four times greater affinity for actinomycin D (AMD) than do viable tumor cells. By using a double labeling technique, we were able to show that, with increasing amounts of AMD bound in cells, the incorporation of RNA precursors is proportionally decreased. However, in the presence of nonviable cells or of native DNA, the AMD-induced inhibition of [3H]uridine incorporation is markedly reduced. This reduction does not occur if DNase is added to the system. The accumulation of dead cells in the tumor vicinity during the natural course of tumor growth or therapy must be taken into consideration in planning therapeutic regimens. We suggest that, in combined chemo- and radiotherapy, increased effectiveness of AMD may be obtained by its use prior to irradiation, thereby assuring its direct access to the tumor cells. The addition of DNase could eliminate or greatly diminish the dead cell competition for the drug.

Response of S 180 murine tumor to bleomycin in combination with radiation and hyperthermia using micronucleus assay: a multimodality approach for therapeutic augmentation.

Response of a transplantable tumor, S180, grown intradermally in inbred Balb/c mice, was assessed by using micronucleus assay after treating the solid tumors with bleomycin (BLM), radiation (RT) and hyperthermia (HT) vis-a-vis multimodality approach. The frequency of micronuclei (MN) though did not vary greatly during the one week of observation in untreated tumors, it significantly increased in the drug and RT groups at 24 hr post-treatment. However, MN frequency was non-significant in the HT group from the control. A drug dose dependent linear increase in the frequency of MN induction was evident in 10, 15 and 20 mg/kg body weight BLM alone treated groups. Combination of radiation with BLM or HT further increased the MN counts in the bimodality groups. But, MN induction at 24 hr post-treatment in the trimodality group (BLM + RT + HT) was non-significant from that of the bimodality treatments. However, the tumors treated with trimodality treatment presented severe tumor necrosis, indicating increased cell loss, and resulting in immediate tumor regression. In all the bi-modality groups MN counts though declined 3 or 5 days post-treatment, the values remained significantly higher than the control, on day 7 post-treatment. Micronucleus assay could be used as a predictive parameter for the assessment of post-irradiation tumor regression response. However, the tumor response assessment with MN assay alone may not be sufficient and the role of other parameters, such as apoptosis and necrosis, in immediate tumor regression, especially radiosensitive/thermosensitive tumors can not be ignored while taking multimodality approach into consideration for cancer therapy.

Effects of oleanolic acid and ursolic acid on inhibiting tumor growth and enhancing the recovery of hematopoietic system postirradiation in mice.

Two triterpene acids, oleanolic acid (OA) and ursolic acid (UA) were examined for their ability to inhibit the tumor growth and modify hematopoiesis after irradiation in three experimental systems: (a) in vivo anti-tumor activity of implanted tumor by ascitic cells was found to be augmented by addition of OA and UA at a high concentration and inhibited in a dose-dependent manner; (b) in the sublethal whole-body irradiated mice treated with the drugs in the 30 min preirradiation period, enhanced effects of OA and UA on peripheral leukocytes were observed by a different significance, and (c) when these chemicals were administered i.p. to mice 30 min before 4 Gy irradiation, both OA and UA enhanced the postirradiation responses of splenic blastogenesis by PHA. UA was a more potent tumorigenic inhibitor than OA. Combining with the gamma-irradiation, however, there was no significant synergetic effect on their anti-tumor activity. The beneficial effects of OA and UA on hematopoiesis and immunocompetence under this study, suggested they might partially play a role in anti-cancer and, furthermore, with the ability to decrease undesirable radiation damage to the hematopoietic tissue after radiotherapy.

[188Re]Rhenium sulfide suspension: a potential radiopharmaceutical for tumor treatment following intra-tumor injection.

Intralesional therapy has been shown to be an effective treatment for tumors. In this study, the suitability of [188Re]rhenium sulfide suspension for tumor treatment following intra-tumor injection was evaluated. The [188Re]rhenium sulfide suspension was radiolabeled with 188Re with a radiochemical yield of more than 96%. In vitro stability studies revealed that more than 99% of the 188Re remained in sulfide form over a 3-day period. After ultrasonication for 5 or 10 min, the main particle size was 1-5 microm. Two [188Re]rhenium sulfide suspensions ultrasonicated for 5 and 10 min, respectively, were injected into separate group of tumor-bearing mice that were killed after specified times to compare the retention of 188Re in tumors and the leakage to different organs by periods and organs removed to gamma counting. The mean retention percentages of 188Re in tumors injected with suspension ultrasonicated for 5 (or 10) min were as follows: 1 h, 90.5 +/- 7.7% (83.1 +/- 13.7%); 24 h, 92.2 +/- 8.6% (83.9 +/- 9.8%); 48 h, 88.3 +/- 10.9% (80.2 +/- 3.8%); and 72 h, 91.5 +/- 7.6% (78.8 +/- 3.0%). Tumor-inhibiting ratio was 96.5%. These results demonstrated that [188Re]rhenium sulfide suspension is an effective radiopharmaceutical for tumor treatment by intralesional therapy.

Changes in the template activity of chromatin isolated from sarcoma-180 ascites cells treated with mitomycin C and gamma irradiation in vivo.

The murine ascites sarcoma 180 cells were used to test the in vivo effectiveness of mitomycin C (MMC) and gamma-radiation applied in combination. The action of intraperitoneal administration of MMC and/or whole-body gamma irradiation on sarcoma 180 tumor bearing Swiss albino mice was investigated by studying the template activity of isolated tumor chromatin. The Km value for transcription of 10 Gy-irradiated chromatin was found to decrease with time implying an increase in the template efficiency with respect to that of the unirradiated control. Maximum decrease in Km was observed after 24 h of irradiation. MMC treatment (7 mg/kg body weight of mouse) for 18 h resulted in an inhibition of the transcription rate. Severe inhibition in the template activity was found when cells were subjected to MMC treatment 18 h prior to irradiation with 10 Gy. Susceptibility of tumor chromatin to DNase II followed the same pattern as observed in the case of transcription indicating structural alteration of the treated chromatin. The data showed that DNA damage and its consequences produced in the ascites cells by prior treatment of MMC were not repaired during the 18 h period after which the application of radiation enhanced cytotoxicity.

Effects of low-dose radiation on tumor growth, erythrocyte immune function and SOD activity in tumor-bearing mice.

BACKGROUND: Activating on mammalian and human body LDR is thought to induce adaptive response, enhance immune function and increase anti-tumor ability. This study was designed to assess the effect of low-dose radiation on tumor growth and on erythrocyte immune function and superoxide dismutase (SOD) activity in tumor-bearing mice. METHODS: Male Kunming mice were subcutaneously implanted with S180 sarcoma cells in the right inguen to create an experimental in situ animal model. Six hours before implantation, the mice were given 75 mGy X-ray radiation, over the body. Tumor size was observed 5 days later while tumor volume was calculated every other day, allowing for the creation of a graph depicting tumor growth. Fifteen days after implantation, the mice were killed to measure tumor weight and observe the necrotic areas and the location of tumor-infiltrating lymphocytes (TILs). Erythrocyte immune function and SOD activity were also determined. RESULTS: Mice pre-exposed to low-dose radiation had a lower tumor formation rate than did those receiving no radiation (P < 0.05). Tumor growth was significantly lower in the mice pre-exposed to low-dose radiation; after 15 days, the average tumor weight in the mice pre-exposed to low-dose radiation was also lower (P < 0.05). Areas of tumor necrosis and infiltration of TILs were larger in the low-dose radiation group than in the non-radiation group. Erythrocyte immune function and SOD activity were higher in the low-dose radiation group than in the non-radiation group (P < 0.05). CONCLUSION: Low-dose radiation can markedly increase the anti-tumor ability of an organism and improve erythrocyte immune function and red blood cell SOD activity as well, suggesting that low-dose radiation might be useful in the clinical treatment of cancer.

Preparation of (188) Re-labeled paper for treating skin cancer.

For homogeneous delivery of beta radiation to skin cancer, we developed a simple method for preparing (188) Re-labeled nitrocellulose paper. The homogeneity and stability of the labeled paper were investigated. Absorbed dose estimates were calculated using the Monte-Carlo method. A 74-MBq (188) Re-labeled paper with 1-cm diameter delivered 147.2 Gy up to 1-mm depth after 2-h irradiation. Animal experiments on tumor-bearing mice showed that 50 Gy is an adequate dose for treating skin cancer. Tumors disappeared 7 days after irradiation in all the groups irradiated by 50 or 100 Gy. The (188) Re-labeled paper provided a convenient, economical, effective, and non-invasive method of treating skin cancer.

[Combination use of lentinan with X-ray therapy in a mouse experimental tumor system (Part I). Basic studies].

Apparent reduction of leukocyte counts was observed in mice irradiated with 1,500 approximately 3,000 rads of X-ray on the left hind leg. This reduction of leukocyte counts was completely protected by the pre-treatment with lentinan before X-ray irradiation. Suppressive effect of X-ray on the antitumor function of lentinan seems to be weak. When treatment with X-ray irradiation and lentinan was applied for mice bearing solid type sarcoma 180, additive effect was obtained by the combination of lentinan before or after X-ray irradiation.

[Effect of UHF frequency on the growth of sarcoma 180]. / Vliianie UVCh-izlucheniia na rost sarkome 180.

Studies performed on mice transplanted sarcoma 180 subcutaneously indicated that the UHF-field of non-thermogenic intensity in multiple (5-10 fold) total irradiation inhibits the tumor growth (T = 60%) and produces a 1.5 times increase of an average survival in tumor-bearing animals. It is suggested that there is a direct relationship between the increased antiblastic function of the body and a stimulating effect of the UHF-field on the immune response in animals.

Involvement of caspase 8 in apoptosis induced by ultrasound-activated hematoporphyrin in sarcoma 180 cells in vitro.

OBJECTIVE: Sonodynamic therapy (SDT), a novel and promising cancer therapy that uses a combination of ultrasound and hematoporphyrin, can induce apoptosis in some cancer cells. However, the mechanism(s) of SDT-induced cell apoptosis is not well understood. This study investigated SDT-induced apoptosis in sarcoma 180 cells. METHODS: Cell suspension were treated by 1.75-MHz continuous focused ultrasound in the presence of hematoporphyrin for 3 minutes, and apoptosis was assessed by flow cytometry, scanning electron microscopy, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling, confocal microscopy, and apoptosis-related protein analysis. RESULTS: DNA breaks, apoptotic bodies, and cleaved poly (adenosine triphosphate-ribose) polymerase were observed 1 hour after SDT. By using laser-scanning confocal microscopy, we found that the Fas-associated death domain and caspase 8 translocated from the cytoplasm to the plasma membrane. Activities of caspase 8 and caspase 3 were detected by an immunohistochemical assay. The results suggested that SDT led to activation of caspase 8, which in turn activated downstream caspase 3. In addition, Z-Ile-Glu-Thr-Asp-fluoromethylketone, a specific inhibitor for caspase 8, was used to confirm the effect of caspase 8 in apoptosis. CONCLUSIONS: Our data primarily show that SDT can induce apoptosis in sarcoma 180 cells in vitro, and caspase 8 may play an important role in SDT-induced apoptosis.

[Evolution of weight and survival of C3H mice with solid, subcutaneous sarcoma 180, treated with radiotherapy, hyperthermia and a combination of hyperthermia and radiotherapy]. / Evolución del peso y supervivencia de los ratones C3H con sarcoma 180sólido subcutáneo, tratados con radioterapia, hipertermia y la asociación de hipertermia más radioterapia.

The authors make an experimental study of the weight evolution and survival rate of sarcoma 180-bearing C3H mice treated by combinations of radiotherapy and hyperthermia. The body weight increased progressively in control animals. The weight increase was less marked under the effect of radiotherapy, hyperthermia, and radiotherapy plus hyperthermia, in decreasing order. While tumor-bearing control animals died after an average of 26.6 days, 3.33, 16.67 and 76.67 per cent of the mice treated respectively by radiotherapy, hyperthermia, and radiotherapy plus hyperthermia were living after 90 days.

Measurements of in vivo effects of an electron-affinic radiosensitizer using a double tracer technique.

In sarcoma-180 of NMRI mice, euoxic tumour cells were labeled with 131I-iododeoxyuridine, and the average tumour cells were labeled with 125I-iododeoxyuridine. An external counting technique permitted in vivo measurements of radiation effects on rates of loss of incorporated activity from the different labeled tumour areas. The technique was employed to study the effect of tumour exposure to gamma irradiation with and without chemical radiosensitization by misonidazole (La Roche 07-0582). Injecting 500 mg/kg of Ro-07-0582 15 minutes before irradiation reduced the measurable oxygen effect by a factor of 1.54. The dose modifying factor evaluated from the 50% tumour regression at 100 days was 1.57.