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PubMed1988

Radiosensitive Down syndrome lymphoblastoid lines have normal ionizing-radiation-induced inhibition of DNA synthesis.

The extent of X-ray-induced inhibition of DNA synthesis was determined in radiosensitive lymphoblastoid lines from 3 patients with Down syndrome and 3 patients with ataxia telangiectasia (AT). Compared to 6 normal control lines, the 3 AT lines were abnormally resistant to X-ray-induced inhibition of DNA synthesis, while the 3 Down syndrome lines had normal inhibition. These results demonstrate that radiosensitive human cells can have normal X-ray-induced inhibition of DNA synthesis and provide new evidence for the dissociation of radiosensitivity from radioresistant DNA synthesis.

Ataxia Telangiectasia↗

PubMed1989

Platinum complexes of triaminotriphenylmethanes: interaction with DNA and radiosensitization.

Complexes of the negatively charged tetrachloroplatinum (II) dianion and the positively charged triaminotriphenylmethane nuclear dyes, Basic Fuchsin and Methyl Green have been prepared. Elemental analysis indicated that the complexes associate as PtCl4(Basic Fuchsin)2 and PtCl4(Methyl Green) in neutral, tight ion pairs. Studies with pBR322 DNA indicated that Pt(Basic Fuchsin)2 and Basic Fuchsin produced no irreversible DNA changes, but that Pt(Methyl Green) readily and Methyl Green less efficiently produced single strand breaks in the DNA. Cytotoxicity studies in exponentially, growing asynchronous EMT6 cells in vitro showed that Pt(Basic Fuchsin)2 was more cytotoxic than Pt(Methyl Green) and that both complexes were more toxic to normally oxygenated than hypoxic cells and to cells at normal vs. acidotic pH (6.45). Radiation studies, also in EMT6 cells, demonstrated that Pt(Methyl Green) was an effective radiosensitizing drug in hypoxic cells (dose modifying factor [DMF] 1.9), but that neither the free dyes nor Pt(Basic Fuchsin)2 had significant radiosensitizing activity. In vivo studies in the FSallC fibrosarcoma confirmed the radiosensitizing properties of Pt(Methyl Green) (DMF 2.7), and indicated that Pt(Basic Fuchsin)2 also had some activity (DMF 1.4) which was equivalent to that of mizonidazole (DMF 1.4). These investigations suggest that these or similar platinum-dye complexes may have important antitumor applications in the human clinic.

Animals↗

PubMed1982

Newly synthesized hypoxia-mediated drugs as radiosensitizers and cytotoxic agents.

Chinese hamster cells in culture were used to compare the radiosensitizing efficiency and cytotoxicity of misonidazole with several 2, 4 and 5 substituted nitroimidazoles. The two substituted compounds (SR 2508 and SR 2555) are similar to misonidazole in radiosensitizing effectiveness, but are significantly less toxic to hypoxic cells. This reduced cytotoxicity may result from either slower drug penetration or slower removal of non-protein sulfhydryl compounds (NPSH). The compound MJL-1-191-VII (a 4-nitroimidazole) is a much more effective radiosensitizer than would be predicted from its electron affinity. It appears to sensitize by two mechanisms, the first resulting from its electron affinity and the second as consequence of its rapid removal of endogeneous cellular NPSH; which are naturally occurring radioprotective substances.

Animals↗

PubMed1983

Radiosensitization of hematopoietic precursor cells (CFUc) in glioblastoma patients receiving intermittent intravenous infusions of bromodeoxyuridine (BUdR).

The potential use of bromodeoxyuridine (BUdR) as a radiosensitizer given by an intermittent intravenous route is being studied in a Phase I/II trial at the National Cancer Institute. In order to assess the extent of radiosensitization, we have studied the radiation response of human bone marrow cells CFUc taken from 6 patients prior to and after a 14-day infusion of BUdR. Varying concentrations (1000-1500 mg) of BUdR were infused for 12 hours every 24 hours for up to 14 consecutive days. Cell survival was determined by colony formation of CFUc in soft agar suspension. X ray survival curves were generated over a dose range of 0-300 rad and the slopes of the survival curves (DO) before and after BUdR infusion were compared. Radiation enhancement ratios (ER) (DO pre-BUdR/DO post-BUdR) ranged from 1.0-2.2 and appeared to be BUdR dose dependent. Above 650 mg/m2, the radiation ER was greater than or equal to 1.5. Dose dependent systemic toxicity to bone marrow and skin was also observed with intermittent intravenous infusions of BUdR. From our study, it appears that an intravenous dose of less than 700 mg/m2/12 hours is well tolerated and may result in radiosensitization of CFUc in man.

Adult↗

PubMed1984

Radiosensitization of hypoxic cells in vivo by SR 2508 at low radiation doses: a preliminary report.

We have used the RIF-1 tumor implanted intradermally in the lower dorsum of C3H mice to explore to what extent the radiosensitizer SR 2508 is capable of sensitizing hypoxic cells at clinically relevant doses of 1 and 2 Gy per fraction. We injected SR 2508 (1000 mg/kg) 45 min prior to each radiation dose in fractionated regimens of 2 or 4 doses/day for up to 5 days (1 or 2 Gy/fraction) given locally to the tumors, which were clamped to occlude the blood supply prior to each radiation exposure. This necessitated the design of clamps which totally occluded blood flow could be applied to nonanesthetized mice without obvious discomfort, and could be applied up to 20 times without compromising the tumor blood supply on removal of the clamps. We have performed various experiments which confirm the validity of these 3 requirements. The response of the tumor cells with and without clamping and with and without SR 2508 was determined by constructing multifraction cell survival curves using the in vivo-in vitro assay. The initial results demonstrate significant radiosensitization of artificially hypoxic tumor cells at 1 and 2 Gy/fraction by SR 2508 (1000 mg/kg). Using the ratio of the D0's of the exponential, multifraction survival curves, we obtained an SER for SR 2508 of 1.6 (3 experiments pooled) compared to an OER (D0 clamped/D0 air-breathing mice) of 2.3 (4 experiments pooled). These data suggest that SR 2508 (and presumably other electron-affinic sensitizers) can radiosensitize hypoxic cells at low radiation doses, and indicate that this and similar drugs may be useful in the radiotherapy of those tumors for which hypoxia limits curability.

Animals↗

PubMed1984

Roles of thiols in cellular radiosensitivity.

Cellular thiols appear to have two separable mechanisms for influencing cellular radiosensitivity: 1) a direct role, through radical scavenging and/or hydrogen donation processes, and 2) an indirect role, regulating the amount of oxygen (or other electron affinic sensitizer) able to reach the radiosensitive targets of the cell. The contribution of each is easily measured with multicell spheroids, using fluorescence activated cell sorting techniques for selective recovery of cells from any depth within spheroids (i.e., from areas with different oxygenation). We have found that the region in the spheroid over which the transition from aerobic to anoxic conditions occurs is highly dependent on cellular thiol levels. Combining thiol depletion by DL-buthionine-S, R-sulfoximine (BSO) and electron affinic radiosensitization using misonidazole resulted in a markedly potentiated response to radiation, which we interpret as being primarily a result of reoxygenation.

Amifostine↗

PubMed1984

Increased radiosensitivity of aerobic mammalian cells following pre-incubation with misonidazole in hypoxia.

The effect of pre-incubation of CHO cells with misonidazole in hypoxia on the aerobic radiosensitivity of these same cells was observed and analyzed according to the concepts of independent and additive interaction. It was found that the sensitivity of cells irradiated in air, in the presence or absence of misonidazole, increased when the cells had been pre-incubated with misonidazole in hypoxia at 37 degrees C. This increase in aerobic radiosensitivity was evident as a loss of the shoulder of the survival curve, and the data were consistent with an additive, rather than an independent interaction mechanism. The effect was also observed when the cells were washed prior to irradiation. These data are consistent with our previous work with hypoxic cells, and support the hypothesis that a toxic metabolite of the sensitizer is produced during hypoxic incubation, whose effect is manifested as an additional increment of cell killing equivalent to an additional dose of radiation. Given the possibility of a diffusible toxic product of sensitizer nitroreduction, the hypoxic cell toxicity of nitroimidazoles, generally perceived to be of importance only in hypoxic cells, may be a factor in the radiosensitivity of non-hypoxic cells in tumours.

Aerobiosis↗

PubMed1984

Pharmacokinetic studies of amino acid analogues of 2-nitroimidazole, new hypoxic cell radiosensitizers.

A series of new analogues of 2-nitroimidazole has been synthesized by inserting various amino acids at 1-position through an amide bond. The ethyl esters of N-alpha-[(2-nitro-1-imidazolyl)acetyl]-L-phenylalanine and N-alpha-[2-nitro-1-imidazolyl)acetyl]-L-tyrosine were found to be the most effective radiosensitizers in vitro against hypoxic Chinese hamster (V-79) cells. The sensitizer enhancement ratios (SER) of these derivatives were 2.2 and 2.3 respectively at 1 mM concentration after 2 hr exposure under hypoxia. However, the free acid of phenylalanine analogue was less active as a radiosensitizer and required 5 mM concentration to produce SER of 1.9. In contrast, the free acid of tyrosine analogue was inactive in this test system. The pharmacokinetic studies with the esters revealed their rapid hydrolysis in serum to the corresponding acids within 5 minutes as detected by HPLC. The pharmacokinetic parameters were therefore determined by employing the free acid analogues and solubilizing them as their sodium salts. The drugs were administered intraperitoneally at 0.5 mg/g dose level to C-57 mice bearing B16 melanoma. These agents were cleared from the plasma rapidly with an apparent t 1/2 of 18.8 and 15.6 min respectively. Peak tumor concentration of approximately 217 micrograms/g was achieved within 15 min with phenylalanine analogue. The tumor to brain ratio was 10:1 suggesting that this agent is excluded from CNS and that the phenylalanine analogue should be considered a potentially less neurotoxic radiosensitizer than misonidazole.

Amino Acids↗

PubMed1984

The use of halogenated thymidine analogs as clinical radiosensitizers: rationale, current status, and future prospects: non-hypoxic cell sensitizers.

The halogenated pyrimidine analogs, bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR) have been recognized as potential clinical radiosensitizers for over two decades. In vivo and in vitro experimental studies document that radiosensitization is directly dependent on the amount of thymidine replacement in DNA by these analogs. Early clinical studies in Japan using selective intra-arterial infusions of BUdR and conventional fractionated radiation suggested improved survival in patients with primary brain tumors, although there were significant catheter-related complications. Based on recent in vivo and clinical pharmacology studies on continuous intravenous infusions of these drugs, clinical trials are underway evaluating the potential of radiosensitization in high grade gliomas and other poorly radioresponsive tumors using the technically safer intravenous route of administration. In this paper, we review the basic strategy for the use of these analogs, the ongoing clinical trials and the potential areas for future experimental and clinical studies.

Animals↗

PubMed1984

A phase I study of the hypoxic cell radiosensitizer Ro-03-8799.

The 2-nitroimidazole hypoxic cell radiosensitizer Ro-03-8799 has been suggested to have possible advantages over misonidazole with regard both to radiosensitization and toxicity on the basis of reported experimental work. The present work reports a Phase I escalating dose toxicity study of the drug. This has shown severe acute central neurotoxicity at high dose levels (greater than 1 g/m2). Initial results of a multiple-dose toxicity study indicate that 1 g/m2 is likely to be the maximum dose which may be given repeatedly. The plasma and tumor pharmacokinetics of the drug have been measured. The mean t 1/2 for 9 patients was 5.8 +/- 1.5 hr. Peak plasma concentration is linearly related to dose and at 1 g/m2 is 12.1 +/- 2.3 micrograms/ml (n = 6). Human tumor drug concentrations have been measured after single doses of 1 g/m2 given to 8 patients with a variety of tumors. Peak tumor concentrations of drug of 11.7-81.6 micrograms/g were found. Because of acute, dose-limiting toxicity related to individual doses it may not be possible to achieve, in human tumors, concentrations of drug that offer significant advantage over misonidazole in terms of radiosensitizing efficiency. No evidence of chronic cumulative toxicity was observed at the doses employed.

Drug Evaluation↗

PubMed1985

Tumor radiosensitization with concomitant bone marrow radioprotection: a study in mice using diethyldithiocarbamate (DDC) under oxygenated and hypoxic conditions.

We have established, both in vitro and in vivo, that Diethyldithiocarbamate (DDC) protects mammalian cells from radiation. The in vivo protection, when non-toxic concentrations of DDC are present one-half hour before irradiation, is reflected by a dose modification factor (DMF) of 1.9 based on LD50/30 and 1.5 using survival of CFUs as an endpoint. Further experiments in vivo have extended our knowledge to the differential radioprotective effects of DDC on the bone marrow of animals breathing room air compared to a 5.5% oxygen in nitrogen mixture. The DMF (LD50/30) for DDC in air breathing animals, previously established as 1.9, can be contrasted with a DMF, obtained in the present study, of 1.2 for animals irradiated in the hypoxic state. Moreover the DMF (CFUs survival) previously established at 1.5 for air breathing animals, can be compared to a value of 1.3, obtained in the present study, for mice irradiated under hypoxic conditions. Modification of the dose response by DDC, for both bone marrow and tumor, was also examined in animals bearing a RIF sarcoma. Although protection of the bone marrow was confirmed (DMF = 2.1), the striking finding was that the tumor cells were sensitized, in both air breathing and nitrogen breathing animals, by the addition of DDC one-half hour before the radiation exposure. Moreover, the tumor radiosensitization, a factor greater than 2, in air breathing animals, appeared to be independent of dose (D0 = 200 rad, with or without DDC). The tumor radiosensitization was even more marked in the nitrogen breathing mice, in which a factor of 10 difference in survival was noted, together with a tendency towards greater sensitization at radiation doses in the clinical range. The results, demonstrating bone marrow radioprotection by DDC (aerobic greater than hypoxic) with concomitant tumor radiosensitization (hypoxic greater than aerobic) strongly suggest a large therapeutic gain factor (TGF) which could be further explored in a clinical setting.

Animals↗

PubMed1986

Radiosensitization by diamide analogs and arsenicals.

Several analogs of the glutathione (GSH) oxidizing reagent diamide [diazenedicarboxylic acid bis(N,N'-diethylamide)] were tested as radiosensitizers of aerobic cells. In general, radiosensitization correlates with the rate of reaction with cellular reducing agents and occurs only when the reductive capacity of the cell is exceeded. SR-4077, [diazenedicarboxylic acid bis(N,N-piperidide)], is particularly suitable for mechanistic studies, because it is less cytotoxic than diamide, but is equally reactive toward cellular GSH. SR-4077 sensitizes CHO cells to X rays under aerobic conditions, even when the drug is added after irradiation. Radiosensitization is expressed both as a change in the exponential slope of the radiation cell survival curve and as a decrease in the shoulder of the survival curve. Phenylarsine oxide, a dithiol-binding reagent, sensitizes aerobic CHO cells to X rays by modification of the shoulder of the survival curve. The results are consistent with the hypothesis that the shoulder-modifying effect of GSH oxidants is caused by the loss of protein thiols, which might be involved in the repair of X ray-induced DNA damage.

Animals↗

PubMed1986

The radiosensitizing and toxic effects of RSU-1069 on hypoxic cells in a murine tumor.

RSU-1069 is one of a group of compounds of particular interest in radiobiology, since it combines the nitroimidazole ring with a side chain bearing a monofunctional alkylating agent. This compound has been shown to be a potent radiosensitizer both in vitro and in vivo. Furthermore, it has recently been shown to be an effective hypoxic cell cytotoxin in vitro. Our studies have been carried out using the SCCVII squamous carcinoma implanted subcutaneously in C3H mice, using a technique we recently developed which facilitates isolation of tumor cell subpopulations from known locations relative to the tumor blood supply. The response of the separated tumor subpopulations was assessed using a soft agar clonogenic assay. For radiosensitization studies, RSU-1069 was administered i.p. at 0.5 mumol/g 20 min before irradiation and the tumors excised 20 min after irradiation. For toxicity studies, tumors were excised 16-18 hr after RSU-1069 administration. The results obtained to date clearly demonstrate that RSU-1069 is an efficient hypoxic cell radiosensitizer and cytotoxin in this murine tumor and has little effect on well perfused (i.e., oxic) cells.

Animals↗

PubMed1986

Radiosensitizing effect of misonidazole in combination with an inhibitor of glutathione synthesis in murine tumors.

The radiosensitizing effects of misonidazole (MISO) in combination with D,L-buthionine-S, R-sulfoximine (BSO), an inhibitor of glutathione (GSH) biosynthesis, were studied in NFSa tumors of C3H/He mice. The radiation response of tumors was assayed by the tumor growth delay time. The GSH contents in tissues were assayed by high performance liquid chromatography (HPLC). GSH content in the tumors decreased to the minimum level (45% of the control), and then gradually recovered to 75% of the control, respectively, 12 and 24 hr after the intraperitoneal injection of 5 mmole/kg BSO. On the other hand, the maximum non-protein sulfhydryl (NPSH) depletion (29% of the control) in the liver of tumor bearing mice was achieved 6 hr after the administration of the same dose of BSO, but fully recovered 24 hr later. When 5 mmole/kg BSO was injected repeatedly 4 times at an interval of 6 hr, GSH content in the tumors decreased to 19% of the control 24 hr after the first injection of BSO. The radiosensitizing effect of 0.5 mmole/kg MISO was markedly increased by this BSO treatment. The enhancement ratio (ER) of this combined treatment was 1.93. On the other hand, ERs of 1.44 and 1.16 were obtained for MISO (0.5 mmole/kg) and for 4 injections of BSO (5 mmole/kg) in combination with radiation, respectively. Although a considerable increase in the radiosensitizing efficiency of MISO in vivo by the treatment with BSO was found without any notable side effects of the combination, more studies on toxicities are needed to get a definite conclusion on the clinical applicability of the combination.

Animals↗

PubMed1986

The radiosensitizing effects of misonidazole (MISO) in combination with diethyl maleate (DEM) in mouse mammary tumors.

Large radiosensitization of C3H/He mouse mammary tumors was obtained with the combination of a non-protein sulfhydryl (NPSH) depletor, diethyl maleate (DEM), and misonidazole (MISO), compared with MISO alone over a range of MISO dose. The difference in enhancement ratios (ER's) for these two treatments was especially prominent at small MISO doses. ER's of 2.06 and 1.44 were obtained, respectively, by combined treatment with DEM (760 mg/kg) and MISO (100 mg/kg) or treatment with MISO alone. Radiosensitization of tumors by DEM alone was observed for doses over 600 mg/kg. When DEM was combined with MISO (100 mg/kg), ER's of the combination were larger than that of MISO alone, for doses over 400 mg/kg of DEM. Similarly, in case of DEM plus MISO (300 mg/kg), the ER's became larger than MISO alone, for doses over 200 mg/kg of DEM. The NPSH content in untreated tumors was 1.08 mmole/kg on the average and no changes in NPSH content was observed after MISO treatment. DEM treatment markedly reduced the NPSH content of tumors as a function of DEM dose and this decrease in NPSH was not significantly affected by MISO treatment. Tumor NPSH was reduced to 24% or less of control by administration of 760 mg/kg of DEM with or without MISO. These results are consistent with competition theory of NPSH and electron affinic radiosensitizers.

Animals↗

PubMed1987

Enhancement of IUdR radiosensitization by low energy photons.

The effect of the photon energy on the radiosensitization produced by iododeoxyuridine (IUdR) was examined using Chinese hamster cells in vitro. Radiosensitization by IUdR was considerably higher for 60 keV photons from 241Am sources than for the 860 keV photons (average energy) from 226Ra sources, under continuous low dose rate conditions applicable to intracavitary brachytherapy (a dose rate of 0.57 Gy/hr). Also, IUdR radiosensitization was higher for 250 kV X rays than for 4 MV X rays under the acute exposure conditions used in external beam radiation therapy (dose rates of 1 to 2 Gy/min). These data support the hypothesis that photons with energies just greater than 32.2 keV, the K-absorption edge of iodine, are more effective in causing cell damage than are photons of other energies, because their absorption results in the production of Auger electron cascades and therefore in the production of high linear energy transfer (LET) radiations.

Americium↗

PubMed1987

Evaluation of incorporated iododeoxyuridine cellular radiosensitization by photon activation therapy.

Halogenated pyrimidines such as iododeoxyuridine (IdUrd), when incorporated into cellular DNA, sensitize cells to radiation. A technique known as photon activation therapy (PAT) has recently been proposed to further enhance IdUrd radiosensitization. This approach relies on the emission of high linear energy transfer Auger electrons as a result of photoelectric absorption of photons with energies slightly above the K shell binding energy for iodine. Thus, additional IdUrd radiosensitization has been predicted for this technique using photons either generated externally from orthovoltage units or with implants of radioisotopes with emissions of the appropriate energy range. We have tested this prediction by comparing the radiosensitization of Chinese V79 cells, which have incorporated IdUrd (16% replacement of thymidine with IdUrd), to megavoltage (15 MV) versus orthovoltage (100 KVp) radiation. Enhancement ratios at 1% survival levels for 15 MV vs. 100 KVp radiation were 1.8 and 1.95, respectively. This modest 10-15% additional enhancement was much less than that predicted by PAT. The discrepancy between experimental data and the theoretical predictions of PAT are discussed.

Animals↗

PubMed1991

The effects of leucovorin and dipyridamole on fluoropyrimidine-induced radiosensitization.

The biomodulators leucovorin and dipyridamole potentiate the cytotoxicity of 5-fluorodeoxyuridine (FdUrd) and 5-fluorouracil (5-FU), respectively. It was hypothesized that these biomodulators would increase fluoropyrimidine-mediated radiosensitization. This hypothesis was tested using cultured HT29 human colon cancer cells. As was predicted, leucovorin increased both FdUrd-mediated cytotoxicity and radiosensitization. The increase in radiation sensitivity was associated with a decrease in the repair of radiation-induced DNA double strand breaks (DSB's). Dipyridamole potentiated the cytotoxicity produced by 5-FU. However, dipyridamole appeared to confer slight protection from irradiation, thus decreasing 5-FU-mediated radiosensitization. This demonstrates that the simple fact that a biomodulator can increase fluoropyrimidine-induced cytotoxicity does not guarantee a corresponding increase in radiation sensitivity. Clinical trials combining fluoropyrimidines and their biomodulators will need to take these potentially complex interactions into account.

Adenocarcinoma↗