Selective internal radiation therapy: Distribution of radiation in the liver

Selective internal radiation therapy for primary and secondary liver cancer involves the intra-hepatic arterial injection of microspheres containing yttrium-90. The microspheres become entrapped primarily in, and thus preferentially irradiate, tumour tissue. During a clinical trial with this therapy it has been possible to take tumour and normal liver tissue samples, after microsphere injection, and measure their specific activity. Absorbed tissue radiation doses were then calculated for tumour and normal tissue samples from a total of nine patients. The mean tumour to normal tissue ratio for radiation dose for the nine patients was approximately 6:1 with a range of 0.4:1–45:1. Injection of similar amounts of activity in different patients resulted in markedly differing tissue doses depending on liver size and tumour burden. Normal liver tissue doses of between 9 and 75 Gy were measured while corresponding tumour tissue doses ranged from 34 to 147 Gy. Selective internal radiation therapy, combined with the blood flow changes resulting from angiotensin II administration, can provide preferentially high radiation doses to tumour tissue within the liver whilst relatively sparing the surrounding normal liver tissue.     

Experimental irradiation of the rat ureter: the effects of field size and the presence of contrast medium on incidence and latency of hydronephrosis

Following X-irradiation of a 1.5 cm length of rat ureter, hydronephrosis developed after doses down to 10 Gy. The estimated ED50 was 11.8 Gy. In the dose range 37.4 Gy to 17.5 Gy there was a significant increase in latency with decreasing dose, but at lower doses the latency did not increase further. Reducing the length of ureter irradiated to 0.5 cm or 0.8 cm caused a decrease in incidence of hydronephrosis and longer latency periods. The ED50 for rats irradiated to 0.5 cm of ureter was 29.6 Gy. The possibility that secondary radiation produced as a result of interaction between X-radiation and iodinated contrast medium might affect the radiation induction of hydronephrosis was investigated. No difference was found between groups of rats irradiated with or without injection of contrast media.     

Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth.

The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 x 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative anti-tumoral effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.     

Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth.

Induction of haem oxygenase-1 (HO-1) as well as nitric oxide (NO) biosynthesis during tumour growth was investigated in an experimental solid tumour model (AH136B hepatoma) in rats. An immunohistochemical study showed that the inducible isoform of NO synthase (iNOS) was localized in monocyte-derived macrophages, which infiltrated interstitial spaces of solid tumour, but not in the tumour cells. Excessive production of NO in the tumour tissue was unequivocally verified by electron spin resonance spectroscopy. Tumour growth was moderately suppressed by treatment with either Nomega-nitro-L-arginine methyl ester (L-NAME) or S-methylisothiourea sulphate (SMT). In contrast, HO-1 was found only in tumour cells, not in macrophages, by in situ hybridization for HO-1 mRNA. HO-1 expression in AH136B cells in culture was strongly enhanced by an NO (NO+) donor S-nitroso-N-acetyl penicillamine. HO-1 mRNA expression in the solid tumour in vivo decreased significantly after treatment with low doses of NOS inhibitors such as L-NAME and SMT (6-20 mg kg(-1)). However, the level of HO-1 mRNA in the solid tumour treated with higher doses of NOS inhibitor was similar to that of the solid tumour without NOS inhibitor treatment. Strong induction of HO-1 was also observed in solid tumours after occlusion or embolization of the tumour-feeding artery, indicating that ischaemic stress which may involve oxidative stress triggers HO-1 induction in the solid tumour. Lastly, it is of great importance that an HO inhibitor, zinc protoporphyrin IX injected intra-arterially to the solid tumour suppressed the tumour growth to a great extent. In conclusion, HO-1 expression in the solid tumour may confer resistance of tumour cells to hypoxic stress as well as to NO-mediated cytotoxicity.     

Induction of the growth arrest and DNA damage-inducible gene GADD153 by cisplatin in vitro and in vivo.

The inability to assess the extent of tumour damage immediately following treatment is a major clinical obstacle to improving the management of cancer patients. Normally, the effectiveness of chemotherapy or radiation therapy cannot be determined for at least several weeks after treatment. We studied the increase in mRNA of the growth arrest and DNA damage-inducible gene GADD153 in human 2008 ovarian carcinoma cells in vitro and in vivo to determine whether treatment-induced increases in the level of GADD153 mRNA could be used as a marker of the extent of tumour damage. GADD153 mRNA was increased in a transient, dose-dependent manner by cisplatin (DDP) when the tumour cells were grown both in vitro and as tumour xenografts in nude mice. The magnitude of induction of GADD153 mRNA did not vary significantly between different 2008 xenografts treated with equal doses of DDP, and GADD153 mRNA induction correlated with the degree of in vitro cytotoxicity for two different schedules of drug exposure. DDP increased GADD153 mRNA levels in melanoma and head and neck xenograft models as well. We conclude that the increase in GADD153 mRNA can be used to detect tumour injury at time points as short as 24 h after administration of DDP.     

Combined interstitial 125I and external X-irradiation on a rat rhabdomyosarcoma

The effect of graded external radiation doses and a dose administered by an implanted 125I seed on growth delay and cure rate of a rat rhabdomyosarcoma was investigated. One 125I seed (0.40 or 0.50 mCi) was implanted per tumour when the tumours had grown to a predetermined size. The irradiation by the 125I seed did not cause significant tumour growth delay. When implantation of an 125I seed was combined with graded external radiation doses, the growth delay observed after these combined regimens was significantly greater than that observed after treatment with external doses alone. The same was observed for tumour cure rates. The effectiveness of the 125I seed could be assessed as being equivalent to a single dose of external radiation of about 6-20 Gy, depending on the external dose applied. The application of 125I seeds combined with external irradiation to obtain local control might be recommended in those cases where the total dose of external radiation alone is limited by normal tissue reactions.     

Enhanced local tumour control after single or fractionated radiation treatment using the hypoxic cell radiosensitizer doranidazole.

OBJECTIVE: This study was designed to assess the potential of the nitroaromatic radiosensitizer doranidazole to preferentially enhance radiation-induced local control in a murine tumour. METHODS: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was used and treated when at 200 mm(3) in size. Doranidazole was dissolved in saline and injected intravenously. Radiation (240 kV X-rays) was locally administered to the tumours or normal feet of restrained non-anaesthetised animals. Response endpoints were local tumour control at 90 days and moist desquamation in foot skin 11-23 days after irradiation. Following logit analysis of the radiation dose-response curves the TCD50 (tumour) or MDD50 (skin) doses (radiation doses producing a response in 50% of treated mice) were estimated and a sensitizer enhancement ratio (SER; ratio of the TCD50 or MDD50 for radiation alone and radiation with drug) calculated. Statistical analysis was performed using a chi(2) test (p<0.05). RESULTS: The TCD50 value (+/-95% confidence interval) for radiation alone as a single treatment was 53Gy (51-55). Injecting doranidazole (200 mg/kg) at 0, 30 or 60 min prior to irradiation significantly enhanced radiation response with the greatest effect seen at the 30-min interval [TCD50=40Gy (37-44); SER=1.3]. No enhancement occurred when the drug was given after radiation. Injecting different drug doses 30 min prior to irradiation showed a dose-response relationship; the respective SERs were 1.1, 1.3 and 1.8 at 50, 200 and 500 mg/kg. In skin, using the 200mg/kg dose and a 30-min interval, the SER was only 1.1. Combining doranidazole and radiation in a fractionated schedule gave a tumour SER of 1.1. CONCLUSIONS: Non-toxic doses of doranidazole significantly enhanced tumour response to single radiation treatments, an effect that was greater than that seen in a normal tissue. It also enhanced radiation given in a fractionated schedule. These effects were similar to those found with misonidazole and nimorazole, nitroaromatic radiosensitizers with clinical efficacy.     

Interactions of Radiation and Cancer Chemotherapeutic Drugs in a C3H Mouse Mammary Carcinoma

The interactions of radiation and adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorour-acil (5-FU), methotrexate (MTX), mitomycin C (MM-C), or cis-diamminedichloroplatinum II (cis-DDP) were studied in a spontaneously arisen C3H mouse mammary carcinoma. The tumour response to drugs alone was evaluated by measuring the tumour growth time defined as the time required for a tumour to reach a volume 5 times that of the treatment day. CTX resulted in a marked tumour growth delay whereas the other drugs had a modest or uncertain effect. In the combined treatment experiments, drugs were administered as single doses either 15 min before or 4 hours after graded single doses of irradiation. The end point for each treatment was the radiation dose which on an average was required to achieve local tumour control in 50 per cent of the mice (TCD_So). The dose effect factor (DEF) was 1.16 for ADM and 1.17 for CTX, the enhanced radiation response being independent of administration before or after irradiation. MM-C also decreased the TCD₅₀ for radiation alone, but its effect was more marked 15 min before (DEF 1.32) than 4 hours after irradiation (DEF 1.18). BLM, 5-FU, MTX, and cis-DDP had no effect on the radiation response neither when administered 15 min before nor 4 hours after irradiation.     

Adjuvant internal radiation therapy in a model of colorectal cancer-derived hepatic metastases.

Selective internal radiation therapy (SIR therapy) is a technique whereby metastatic liver cancer is irradiated by embolising microspheres containing the radionuclide yttrium-90 into the hepatic arterial circulation. To date this technique has not been used as an adjuvant therapy, but rather to treat established metastases in the liver. This study evaluated the use of two intrahepatic radiation doses delivered on radioactive microspheres for the treatment of small, growing micrometastases. Three groups of five rats were each inoculated with tumour spheroids into the portal vein. The resultant liver micrometastases were treated with either 10 or 20 MBq of yttrium-90 microspheres or a sham dose of non-radioactive microspheres injected into the portal vein 2 days following tumour inoculation. The livers of each animal were examined for the presence of metastases after a further 21 days and liver function tests were performed. At the time of sacrifice there was no obvious normal liver damage in any of the rats treated with microspheres. The livers of the sham-treated animals contained extensive signs of tumour deposition. A mean of 34 tumours were taken from the livers of each of the sham-treated animals, whereas only a single tumour was found in one animal treated with 10 MBq of yttrium and eight small tumours from two animals treated with 20 MBq. Liver function tests demonstrated a significant short-term increase in alkaline phosphatase levels in the radiation-treated animals compared with shams, but there were no other indications of any effects on liver function. These results indicate a potential role for SIR therapy in an adjuvant setting with colorectal cancer.     

Colorectal carcinoma in a rat model: suppression of tumour development and altered host immune status following treatment with anti B-lymphocyte serum

The rate of colonic tumour development and immune capability in rats whose B-lymphocyte function was suppressed by injections of rabbit anti-rat IgM and also given the carcinogen dimethylhydrazine (DMH) were studied. Four rat groups were arranged to receive either DMH + anti-IgM, DMH + normal rabbit serum (NRS), saline + anti-IgM, or saline + NRS. Tumour weight, blood and mesenteric lymph node B-lymphocyte numbers, in vivo allograft response, in vitro lymphocytotoxicity, and leucocyte migration inhibition response (LMI) were recorded fortnightly. Tumour induction was delayed in the DMH + anti-IgM (treated tumour) group, which developed less tumour than the DMH + NRS (untreated tumour) group (p less than 0.001). Spleen cell lymphocytotoxicities were depressed in treated rats when compared to either the saline + anti-IgM (treated control) rats or the untreated rats (P less than 0.02), whereas anti-IgM treatment suppressed lymphocytotoxicity responses in control rats (p less than 0.05). The untreated tumour rats were tumour immune by LMI; however, the treated tumour rats did not express this in vitro tumour immunity. The B-lymphocyte levels in the mesenteric lymph nodes of untreated tumour rats increased with tumour induction (p less than 0.05), whereas in the treated tumour rats B-lymphocyte levels were not similarly stimulated.     

ICRF-159 enhancement of radiation response in combined modality therapies. I. Time/dose relationships for tumour response.

The combined effect of the chemotherapeutic agent ICRF-159 and irradiation were evaluated using the Lewis lung tumour (LL). At a daily dose of 25 mg/kg, ICOF given alone prevented the progressive growth of LL. Daily pretreatment also potentiated the effects of radiation (600 rad) on tumour growth, provided the pretreatment kinetics of the tumour permitted a response to radiation alone. Single acute doses of the drug failed to alter the growth of LL, and when combined with radiation failed to enhance the radiation effect. Fractionation of the drug (25 mg/kg; 4 doses at 3h intervals) before irradiation, however, results in immediate effects on tumour growth which are more than additive. The results suggest that a low dose of ICRF-159 for extended periods is more effective in enhancing radiotherapy than a high dose provided acutely.     

Minimally-invasive debulking of ovarian cancer in the rat pelvis by means of photodynamic therapy using the pegylated photosensitizer PEG-m-THPC

Interstitial photodynamic therapy (PDT) using the pegylated photosensitizer PEG-m-THPC was evaluated as a minimally-invasive procedure to selectively debulk unrespectable pelvic ovarian cancer (NuTu-19) in immunocompetent rats. To assess tumour selectivity, PEG-m-THPC at dosages of 0.3, 3.0 and 30 mg kg(-1) body weight was administered intravenously to 30 rats 4 weeks following tumour induction. Eight days later laser light at 652 nm and optical doses ranging from 100 to 900 J cm(-1) diffuser-length was delivered by an interstitial cylindrical diffusing fibre inserted blindly into the pelvis. Three days following light application, the volume of necrosis was measured and the damage to pelvic organs was assessed histologically on cross sections. For analysis of survival, 20 tumour-bearing rats received PDT using drug doses of 3 or 9 mg kg(-1) body weight and an optical dose of 900 J cm(-1) diffuser-length, whereas ten untreated tumour-bearing rats served as controls. The histological assessment of PDT induced necrosis showed a non-linear dose-response for both the photosensitizer dose and the optical dose. The lowest drug dose activated with the highest optical dose did not induce more necrosis than seen in tumour-bearing control animals. The same optical dose induced necrosis of 17 mm in diameter using 30 mg kg(-1) and 11 mm using 3 mg kg(-1) photosensitizer. The optical threshold for induction of significant necrosis was between 100 and 300 J cm(-1) diffuser-length for 30 mg kg(-1) and between 300 and 500 J cm(-1) for 3 mg kg(-1) PEG-m-THPC. Significant damage to normal pelvic organs was only seen if 30 mg kg(-1) photosensitizer was activated with optical doses of 700 J cm(-1) or more. In the survival study, all treated animals survived PDT for at least 2 weeks and the intestinal and urinary tract remained functional. No clinical signs of blood vessel or nerve injury were observed. Mean overall survival of untreated tumour-bearing rats was 25.0 +/- 4.5 days compared to 38.4 +/- 3.8 days and 40.0 +/- 3.6 days for rats treated with 3 mg kg(-1) or 9 mg kg(-1) PEG-m-THPC mediated PDT respectively (P < 0.05). We conclude that PEG-m-THPC mediated PDT has a favourable therapeutic window and that this minimally-invasive procedure can reduce pelvic cancer bulks effectively and selectively.     

Manipulation of body fat composition with sterculic acid can inhibit mammary carcinomas in vivo

Sterculic acid, a delta-9-desaturase inhibitor, administered to rats caused a rise in the stearic:oleic acid ratio of total lipids in peripheral red cells, serum and liver (P less than 0.001). As a reduction in the stearic:oleic acid ratio has been described in cancer cells, we investigated the effect of sterculic acid on tumour growth. Female F344 rats were injected subcutaneously with two different doses of sterculic acid for 4 weeks prior to, and 4 weeks following, implantation of a nitrosomethylurea-induced mammary tumour. Tumour growth was inhibited equally by the two doses of sterculic acid (P less than 0.001). A rise in the stearic:oleic acid ratio of tumours was observed in rats treated for only 16 days with sterculic acid. Manipulation of the tissue stearic:oleic acid ratio inhibits transplanted mammary tumour growth in rats.     

Tritium uptake, half-lives and radiation doses in tissues of cancer patients treated with tritiated 2-methyl-1:4-naphthaquinol diphosphate

Comparisons of the uptake into tumour biopsies 30 min after intravenous or intra-arterial injections showed that tumours of gastrointestinal origin took up significantly greater amounts of the tritiated drugs than did any other group of tumours, and with other types of tumours some individual biopsies showed very high tumour specific activities after intra-arterial injections. The tritium in the tumour disappeared by two exponential decay processes, one with a half-life of 1.35 days and the other with a half-life of 14.4 days. The ratio of the concentration of the long-lived component to that of the short-lived component was 0.33. Tritium estimations on normal tissues taken at autopsy from patients who received only one injection of the tritiated drug showed that the biological half-life in normal tissues ranged from 5.7 days (heart) to 34.5 days (long-lived component in brain). The initial specific activity in μc/g for each c/kg injected ranged from 71 (long-lived component in brain) to 505 (kidney). After a single injection of 1 c of the drug per kg body weight, the greatest doses of radiation were received by the kidney (1,600 R), testis (1,300 R), liver (1,050 R) and brain (990 R). The lowest doses were received by skeletal muscle (395 R) and bone marrow (604 R). The radiation dose in the tumour depends on the initial concentration and the half-life in the tumour. Initial tumour concentrations of 5–8 mc/g wet tissue should give radiation doses in the therapeutic range after a single injection.     

Second neoplasms following megavoltage radiation in a pediatric population.

Previous reports of radiation-related neoplasia have relied primarily upon patients treated by orthovoltage to low doses for benign disease. This survey is believed to be the first to assess the incidence of second neoplasms following megavoltage therapy. The source was the records of all long-term pediatric survivors (88 patients) who were treated with megavoltage radiation (cobalt 60) at the University of Minnesota. There was an average follow-up period of 14 years during which 7 second neoplasms were discovered (8%). Five were not associated with prior radiation. Both radiation-related neoplasms were associated with low doses and one was without significant morbidity. Two of the seven neoplasms were malignant; one was not associated with radiation while the other was associated with prolonged chemotherapy and low dose radiation (1%). The only fatal second neoplasm was not associated with radiation but developed 5 years after prolonged chlorambucil treatment. This review reveals the tendency of childhood cancer victims to develop other neoplasms regardless of radiation. The finding of neoplasia induction only at low radiation doses supports the Gray hypothesis of decreased tumor induction at high doses through increased cell killing.     

Metastasis and the excision of irradiated LMCI tumours in the rat

Lymph node metastases occurring within 150 days of local non-curative irradiation and excision of a transplantable mammary adenocarcinoma (LMCI) have been scored and their growth measured in isogeneic rats. Single doses (5-40 Gy) of 60Co gamma-rays were given to the primary at 8-10 mm diameter and these were excised either immediately or up to 30 days later. From the results it is concluded that approximately half of all rats have occult dissemination at the time of irradiation. Only these form metastases after the early excision of 10-40 Gy treated tumours but the number of positive sites per animal is significantly reduced. Delayed excision of the irradiated primary permits the further seeding of metastases and, with its regrowth, the incidence of positive rats and the mean number of metastases per animal is restored to that observed after control surgery. This process was dependent on the radiation-induced delay in growth of the primary tumour. However, all metastases, irrespective of site, radiation dose, and time of primary tumour excision showed a growth rate characteristic of the untreated LMCI tumour. No evidence was obtained for an enhancement in the dissemination of metastatic cells from the irradiated but regrowing primary tumour. However, an alteration in the pathways of lymphatic dissemination leading to an increased number of metastases seeding the mediastinum and abdominal lymph nodes may have occurred.     

Radiation induction of drug resistance in RIF-1: correlation of tumor and cell culture results

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.     

Further evaluation of nicotinamide and carbogen as a strategy to reoxygenate hypoxic cells in vivo: importance of nicotinamide dose and pre-irradiation breathing time.

The combination of nicotinamide and carbogen breathing is awaiting clinical evaluation as a strategy to overcome tumour hypoxia and thus enhance radiation response. We have continued our evaluation of this approach in the murine SCCVII tumour with the aim of determining the importance of nicotinamide dose and the pre-irradiation breathing time (PIBT) for carbogen. For carbogen breathing alone maximal enhancement of radiation response was observed with PIBT''s of between 5 and 30 min. When nicotinamide (1,000 mg kg-1 IP) was administered 60 min prior to irradiation little or no variation in radiation response was observed for all the PIBT''s examined (5-90 min). Indeed at all PIBT''s the cell survival obtained for the carbogen nicotinamide and radiation combination was indistinguishable from that expected for a fully aerobic response. For PIBT''s of 15 and 60 min we examined the influence of nicotinamide doses between 50 and 1,000 mg kg-1. Significant radiosensitizing effects were observed for all nicotinamide doses tested above 50 mg kg-1. Moreover for doses of 250 mg kg-1 and above the cell survival data was consistent with that expected for a fully aerobic response. No additional benefit accrued from raising the nicotinamide dose above 250 mg kg-1. These results indicate that significant radiosensitization may be expected even with clinically achievable nicotinamide doses when it is combined with carbogen breathing. Furthermore, the use of nicotinamide may reduce the critical importance of PIBT on the radiosensitization observed with carbogen.     

Cadmium exposure in rats and tumours of the prostate.

Recently, we completed three chronic studies in rats indicating that cadmium exposure can induce tumours of the prostate. In the first study, s.c. cadmium exposure increased prostatic tumour incidence only at doses below the threshold for cadmium induction of testicular dysfunction (5.0 mumol/kg). In a second study, prostatic tumours were elevated at higher doses of cadmium (30 mumol/kg, s.c.) if testicular dysfunction was prevented by zinc treatment. Finally, dietary cadmium (25-200 micrograms/g) increased prostatic neoplastic lesions. Thus it appears that cadmium produces prostatic tumours only if testicular function is maintained. Accumulation and retention of prostatic cadmium appears to be highly androgen-dependent. Furthermore, metallothionein, a protein associated with tolerance to cadmium, may be deficient in the rat prostate, and the prostatic metallothionein gene, at least in the ventral lobe, may be unresponsive to metal stimuli. The finding of prostatic cancer in cadmium-treated rats clearly supports a possible role for exposure to cadmium in human prostatic cancer.     

Radiosensitization of tumours by porphyrins

Our previous data indicate, that hematoporphyrin dimethyl ether (HPde) can totally inhibit the growth of aggressive Ehrlich ascite tumour, when combined with low doses (2Gy) of ionizing radiation. Taking into account these findings, it appears of particular interest to evaluate the dependence of radiosensitizing efficiency of porphyrins on tumour aggressiveness. For this purpose two experimental tumour models (aggressive murine Ehrlich ascite carcinoma, (EAT), and not-aggressive hepatoma MH-22A) were used. Moreover, radiosensitizing properties of three porphyrin-type compounds of different chemical heterogeneity were evaluated (hematoporphyrin dimethyl ether (HPde), photofrin II (PII) and hematoporphyrin derivative (HPD)). Data obtained indicate, that HPde is the most effective one in this context (HPde>PII>HPD). It is important to note, that only the aggressive EAT tumours were radiosensitized by these dyes. No signs of radiosensitization (inhibition of tumour growth, injury of tumour tissue, evaluated by histological analysis) were observed in not-aggressive MH-22A hepatoma. Moreover, it was shown, that ligands of peripheral benzodiazepine receptors (PBR) might diminish the cell growth in aggressive EAT, but not in not-aggressive MH-22A hepatoma. The mechanism of radiosensitization by porphyrins, proposed in our previous studies, was strongly confirmed by these data. Actually, dicarboxylic porphyrins, being ligands of PBR, which are highly expressed in just aggressive tumours, can inhibit tumour cell proliferation and act in concert with ionizing radiation. Thus, combination of porphyrin and ionising radiation reflects the action of two antiproliferative factors, what eventually increases the response of aggressive tumours to the low doses of ionising radiation.