Effect of membrane fatty acid composition on radiosensitivity of V79 Chinese hamster cells.

Exponentially growing V79-379A Chinese hamster fibroblasts were transferred to low-lipid medium enriched with a single fatty acid of the C18 series. After 24 h at 37 degrees C, the fatty acid composition was determined by gas chromatography of the corresponding methyl esters for the total lipid extracts of the cells and for the nuclear membrane fraction. Radiation survival curves, based upon a clonogenic assay, were obtained by irradiation with low dose-rate 60Co gamma rays at either 4 degrees C or room temperature. We observe no effect of fatty acid upon radiosensitivity of these cells at either temperature, in confirmation of published reports with other mammalian cell lines.

Mechanism of cholesterol side-chain cleavage. II. The enzymic hydroperoxide-glycol rearrangement of the epimeric 20-hydroperxycholesterols in 18O-enriched water.

Incubation of 20 alpha-hydroperoxycholesterol (I) and its 20 beta-isomer, 20 beta-hydroperoxy-20 isocholesterol (II) with adrenocortical mitochondrial preparations in the absence of molecular oxygen, in normal and 18O-enriched water, gave 20 alpha, 22R-dihydroxycholesterol (III) from I and 20 beta,21-dihydroxy-20-iso-cholesterol (IV) from II. Mass spectral analysis of the persilylated glycol products III and IV showed no uptake of 18O, indicating that the oxygen atoms of the C20-, C22- and C21-hydroxyl groups originated from the 20-hydroperoxy atomic oxygen complex is the intermediate in the enzymic oxidative reactions of cholesterol side-chain cleavage.

Efficacy and mechanism of aluminium phthalocyanine and its sulphonated derivatives mediated photodynamic therapy on murine tumours.

The efficacy of photodynamic therapy (PDT) mediated by aluminium phthalocyanine (AlPc) and its mono- and disulphonated derivatives (AlPcS1 and AlPcS2, respectively) on murine EMT-6 tumour were compared in vivo. AlPc (0.25 mumol/kg) PDT resulted in no tumour recurrence in all treated mice. In contrast, PDT with AlPcS1 (2 mumol/kg) and AlPcS2 (1 mumol/kg) only produced tumour cure in 75% and 86% of mice, respectively. Immediately after AlPc-PDT, tumour cells were found to be viable as determined by in vitro clonogenicity, but progressive cell death occurred thereafter. In contrast, AlPcS1 and AlPcS2 PDT produced substantial cell death (approximately 35% and 70%, respectively, of entire tumour) immediately after phototherapy, and yet further loss of tumour cell viability continued after PDT. In all cases, few vascular effects were observed at 0 h post-PDT, as indicated by the retention of 99mTc-MIBI in the tumour. However, the reduction of blood flow in tumours progressed with time, such that blood flow in tumours fell to approximately 25% of the control level by 24 h after both AlPc and AlPcS1 PDT. With AlPcS2, there was only an approximate 50% fall in tumour blood flow by 24 h. These results demonstrate a greater PDT efficiency with AlPc on tumour destruction, which is an indirect mechanism involving damage of tumour vasculature, whereas AlPcS2 has a greater effect on direct tumour cytotoxicity and AlPcS1 exerts both direct and indirect modes of action against tumours.

Photosensitized reactions of nucleic acids.

The main effects of near-ultraviolet and visible light on cellular DNA are reviewed with emphasis on base lesions, oligonucleotide single-strand breaks and DNA-protein cross-links. Model system photosensitization reactions of DNA are also discussed. This includes photodynamic effects, menadione-mediated photooxidation, photoionization of antibiotics, the photochemistry of 5-halogenopyrimidines and urocanic acid.

Synthesis of A-ring fluorinated derivatives of (17 alpha,20E/Z)-[125I]iodovinylestradiols: effect on receptor binding and receptor-mediated target tissue uptake.

We have prepared a series of 2- and 4-fluoro derivatives of the isomeric (17 alpha,20E)- and (17 alpha, 20Z)iodovinylestradiols (IVE2) and also the analogs substituted with either a 7 alpha-methyl (7 alpha-Me-IVE2) or 11 beta-methoxy group (11 beta-OMe-IVE2) and evaluated their in vitro and in vivo properties. Electrophilic substitution of the estrone derivatives with N-fluoropyridinium salt gave the 2- and 4-fluoro analogs which were subsequently converted to the 17 alpha-ethynyl derivatives. The tributylstannyl intermediates were obtained from the corresponding 17 alpha-ethynyl analogs using azobisisobutyronitrile or triethylborane as catalyst. All 12 products were also prepared as their no-carrier-added [125I]iodovinyl analogs via destannylation of the tributylstannyl precursors. Binding affinity for the estrogen receptor (ER) was in general higher for the 4-F derivatives as compared to the 2-F derivatives, while the 20Z isomers of the same compounds showed somewhat higher ER binding affinity as compared to the 20E isomers. The combination of an A-ring fluoro and 7 alpha- or 11 beta-substituent decreased ER binding affinity. Substitution of a fluoro atom at C-4 on either the 17 alpha-ethynylestradiol or isomeric 17 alpha-IVE2 enhanced the affinity of the parent molecule for the ER. A-ring fluorination of all other analogues tested had no effect or depressed ER binding affinity. Varying incubation conditions showed substantial differences in ER binding kinetics between the 20E and 20Z isomers. Tissue distribution in immature female rats showed that the highest uterus uptake and uterus to blood/nontarget ratios in the IVE2 series were obtained with the 4-F-(17 alpha,20Z)IVE2 isomer. The combination of A-ring fluoro and 7 alpha- or 11 beta-substitution decreased uterus uptake but had little or no effect on uterus to blood/nontarget ratios. The highest uterus to blood ratios were observed for the 4-F-(17 alpha,20E)11 beta-OMe-IVE2 (75 at 6 h and 125 at 12 h pi) reflecting rapid blood clearance and in vivo stability, as confirmed by the low levels of thyroid radioactivity. The lack of correlation between ER binding affinities and uterus uptake, and/or uptake ratios, suggests that other factors, including nonspecific binding and metabolic processes, also are involved in the tissue localization process. Our data suggest that 4-F substitution onto (17 alpha,20Z)IVE2 and (17 alpha,20E)11 beta-OMe-IVE2 enhances the potential of these compounds to function as SPECT imaging agents of ER-rich tissues.

Synthesis and structure-affinity of a series of 7 alpha-undecylestradiol derivatives: a potential vector for therapy and imaging of estrogen-receptor-positive cancers.

A series of 7 alpha-undecylestradiol derivatives, featuring various substituents at the end of the undecyl spacer chain, were synthesized and evaluated for their interaction with the estrogen receptor and nonreceptor sites. Their relative binding affinities (RBA) for calf uterine estrogen receptors were measured by competitive binding assays and varied between 0.5 and 8.4% of that of unlabeled 17 beta-estradiol. Enhanced lipophilicity and steric hindrance of the substituent on the end of the spacer chain resulted in decreased binding affinity for the estrogen receptor, while interactions with nonreceptor sites increased. RBA values were not affected by prolonged incubation times, suggesting a stable ligand-receptor complex. The potential to use the 7 alpha-undecylestradiol as a vector for site-selective delivery of diagnostic and therapeutic moieties to estrogen-receptor-positive human cancers is discussed.

7 alpha-Methyl- and 11 beta-ethoxy-substitution of [125I]-16 alpha-iodoestradiol: effect on estrogen receptor-mediated target tissue uptake.

The 7 alpha-methyl and 11 beta-ethoxy derivatives of 16 alpha-[125I]iodoestradiol were prepared via halogen exchange with 125I of the corresponding 16 beta-bromoestradiol precursors. The 16 alpha-bromo derivatives were obtained via halogenation of the analogous 17-enol acetate, epimerization to the 16 beta-isomer, and hydride reduction. Stereochemical assignments were based on high resolution 1H NMR. To evaluate the effect of the nature and stereochemistry of the 16-halo substituent on the relative binding affinity for the estrogen receptor, the analogous 16-chloro derivatives were also prepared. The highest binding affinities were observed with the 7 alpha-methyl-16 alpha-haloestradiols, particularly the bromo and chloro derivatives while the 16 alpha-iodo derivatives gave somewhat lower values. Both the 11 beta-ethoxy and 7 alpha-methyl-16 alpha-[125I]iodoestradiols localize in the uteri of immature female rats via a receptor-mediated process. Rapid blood clearance of the 125I-labeled 7 alpha-methyl derivative results in lower 125I uptake by the uterus as well as nontarget organs as compared to the 11 beta-substituted estradiol analogs. However, uterus to blood and nontarget ratios are more favorable for the 7 alpha-methyl-16 alpha-[125I]iodoestradiol as compared to the analogous 11 beta-ethoxy derivatives suggesting that this compound substituted with 123I may be useful for the in vivo imaging of estrogen receptor-rich breast tumors by single photon emission computerized tomography.

2- and 4-fluorinated 16 alpha(-)[125I]iodoestradiol derivatives: synthesis and effect on estrogen receptor binding and receptor-mediated target tissue uptake.

The effect of 2- and 4-fluoro substitution on the estrogen receptor-mediated tissue localization of radioiodinated 16 alpha-iodoestradiol (16 alpha-IE2) and its 11 beta-methoxy analogue (11 beta-OMe-16 alpha-IE2) was evaluated. Electrophilic substitution of estrone or 11 beta-methoxyestrone with N-fluoropyridinium salt gave the 2- and 4-fluoro derivatives which were subsequently converted to the 3,17 beta-enol diacetate and brominated to yield exclusively the 16 alpha-bromo analogues. Epimerization gave the corresponding 16 beta-bromoestrones which were reduced to the 17 beta-hydroxy derivatives. Halogen exchange with NaI or Na[125I]I provided the A-ring fluorinated 16 alpha-iodoestradiols. The 4-F analogue exhibited higher affinity for estrogen receptors than the corresponding 2-F analogue, and these differences were more pronounced at higher incubation temperatures. Biodistribution studies in immature female rats showed that 4-fluoro substitution had only a moderate effect on receptor-mediated tissue uptake of the parent molecules whereas 2-fluoro substitution resulted in strongly diminished tissue specificity. The lower target selectivity of the 2-F, compared to the 4-F, analogue correlates to some extent with their different receptor binding properties; however, the rate of catabolism may also be involved. Differences in blood clearance further accentuated the localization properties to yield particularly high uterus to blood ratios in the case of the 4-F-11 beta-OMe-16 alpha-IE2, suggesting the potential of the analog labeled with 123I as a radiopharmaceutical for receptor imaging in nuclear medicine. The isopotential maps of the fluorinated steroids, obtained via semiempirical computer modeling on the molecular structures, show striking differences between the 4-F and 2-F derivatives reflecting their varying biological properties.

Synthesis, receptor binding, and tissue distribution of (17 alpha,20E)- and (17 alpha,20Z)-21-[125I]iodo-19-norpregna-1,3,5(10), 20-tetraene-3,17-diol .

The isomeric (17 alpha,20E)- and (17 alpha,20Z)-(iodovinyl)estradiol derivatives 3 and 6, and their no-carrier-added (nca) [125I]iodovinyl analogues, were tested for their relative target tissue retention and binding affinity for the estrogen receptor. The (iodovinyl)estradiols 3 and 6 were prepared via destannylation of the (17 alpha,20E)- and (17 alpha,20Z)-tributylstannyl precursors 2 and 4 with retention of configuration. Selective formation of the E or Z isomers 2 and 4 during the reaction of 17 alpha-ethynylestradiol 1a with tri-n-butyltin hydride was controlled by the presence or absence of the catalyst, the polarity of the solvent, and the reaction temperature. The nca [125I]iodovinyl analogues [125I]-3a and [125I]-6a were obtained in good radiochemical yield and high purity by treatment of 2a and 4a with [125I]NaI in the presence of H2O2 and chloroamine-T, respectively. Of the two isomeric iodovinyl derivatives 3 and 6, the 20Z isomer 6a exhibited the highest receptor binding affinity and the [125I]-6a gave the highest in vivo receptor-mediated target tissue uptake.

Synthesis, receptor binding, and tissue distribution of 7 alpha- and 11 beta-substituted (17 alpha,20E)- and (17 alpha,20Z)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-diols.

The 11 beta-methoxy, 11 beta-ethoxy, and 7 alpha-methyl derivatives of the isomeric (17 alpha,20E)- and (17 alpha,20Z)-(iodovinyl)estradiols 3 and 6, and their no-carrier-added [125I]iodovinyl analogues, were evaluated for their relative target-tissue retention and binding affinity for the estrogen receptor. The isomeric iodovinyl and [125I]iodovinyl derivatives were prepared via destannylation of the corresponding tributylstannyl precursors in the presence of H2O2 or chloramine-T, with retention of configuration. The 20Z isomers 6 exhibited slightly higher receptor binding affinities than the 20E isomers 3, with all eight isomeric products giving relative binding affinity values in the 20-50 range. The 11 beta- and 7 alpha-substituted (iodovinyl)estradiols gave substantially higher estrogen receptor-mediated uterus uptake as compared to the nonsubstituted parent molecule. Synergism between the effect of 11 beta- or 7 alpha-substituents and the configuration of the iodovinyl group was evident from the in vivo distribution pattern of [125I]-3 and -6. The best uterus uptake was observed, at 2 h postinjection, with the 20E isomer of 11 beta-methoxy derivative 3b. However, at 5 h postinjection the 20Z isomer 6b reached higher uterus concentrations than the 20E isomer 3b, and furthermore, these values are now comparable to those observed with the 20Z isomer of the 11 beta-ethoxy derivative 6c. In the case of the 7 alpha-methyl derivatives the differences in in vivo stability between the 20E and 20Z isomers was less pronounced, whereas the 20Z isomer 6d reached somewhat higher uterus to blood as well as nontarget ratios.

Quantitative structure-activity relationships/comparative molecular field analysis (QSAR/CoMFA) for receptor-binding properties of halogenated estradiol derivatives.

The 3-D quantitative structure-activity relationships/comparative molecular field analysis (QSAR/CoMFA) paradigm, which considers the primary importance of the molecular fields in biological recognition, is now widely used to analyze and predict receptor-binding properties of various ligands. CoMFA was applied to build 3-D QSAR models of substituted estradiol-receptor interactions, employing 3-D molecular databases of more than 40 molecules. Ligands included the 17 alpha-ethynyl- and isomeric 17 alpha (20E/Z)-(iodovinyl)estradiols and their 7 alpha-, 11 beta-, and 12 beta-methyl (-methoxy) and -ethyl (-ethoxy) derivatives as well as selected 2- and 4-halogenated analogs. The influence of different CoMFA descriptors was studied in order to achieve the highest possible cross-validated r2, as derived from partial least-squares calculations. Special emphasis was put on the analysis of the nature of H-bonding (donor/acceptor) interactions. The model with the best predictive performance (r2 = 0.895) was used to visualize steric and electrostatic features of the QSAR (standard deviation*coefficient contour maps) and to predict receptor-binding affinities (RBA) of substituted estradiols other than those included in the original database. Twenty-seven test molecules were selected, including five which had previously been reported by other investigators. For the latter, a very good correlation with literature RBA values was obtained, which together with the high cross-validated r2 provides evidence for the high predictive capacity of the model. Among the unknown structures, the model suggests several new substitutions to derive at reasonable affinity ligands for the estrogen receptor.

Synthesis, receptor binding, and target-tissue uptake of carbon-11 labeled carbamate derivatives of estradiol and hexestrol.

The reaction of ethyl chloroformate with amino compounds has been evaluated as a simple route to carbon-11 labeling of steroid hormone-receptor-based imaging agents. Both a 17 beta-amino analogue of estradiol and an aminoethyl derivative of the nonsteroidal estrogen hexestrol with potential affinity for the estrogen receptor were studied. The unlabeled carbamate derivatives of the amino estrogens were prepared by standard methods, and the 11C-labeled analogues were synthesized from [11C]ethyl chloroformate, generated by purging ethanol with [11C]phosgene. Both carbamates showed weak in vitro binding affinity for the estrogen receptor, and only the 11C-labeled hexestrol exhibited a small but significant estrogen-responsive uterus uptake in immature rats.

Hydroxyphthalocyanines as potential photodynamic agents for cancer therapy.

A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.

Syntheses and photodynamic activities of novel trisulfonated zinc phthalocyanine derivatives.

The synthesis of water-soluble, unsymmetrical, trisulfonated zinc phthalocyanines (ZnPcS3) as single products of the ring expansion of boron tri(4-sulfo)subphthalocyanine (SubPc) is reported. The novel, water-soluble trisulfo-SubPcB(OH) was prepared via hydrolysis of the tris(4-chlorosulfonyl)SubPcB(Br) which in turn was obtained from the condensation of 4-(chlorosulfonyl)phthalonitrile with BBr3 in 1-chlorobenzene. A number of ZnPcS3 analogues were prepared via the reaction of S3SubPcB (OH) with different diiminoisoindoline derivatives of increasing hydrophobicity. The reaction proceeds at relative low temperature with acceptable yields. Metalation of free base Pc's with zinc acetate dihydrate afforded the corresponding zinc complexes. Photodynamic activities were measured against the EMT-6 mouse mammary tumor cell line and compared to those of the known ZnPcS3 and ZnPcS4. Added (t-Bu)benzo and (t-Bu)naphtho groups increased the in vitro cell photoinactivation efficacy of the ZnPcS3, whereas addition of a fourth sulfobenzo or bulky diphenylpyrazino group decreased the activity of the parent molecule. The (t-Bu)naphthotrisulfobenzoporphyrazine induced the best in vivo photodynamic tumor control which, combined with its good solubility and broad absorption spectrum, renders this compound an interesting dye for photodynamic applications in medicine.

Synthesis and photodynamic activities of silicon 2,3-naphthalocyanine derivatives.

Bis(tert-butyldimethylsiloxy)- (7), bis(dimethylthexylsiloxy)- (8), bis(tri-n-hexylsiloxy)- (9), and bis(dimethyloctadecylsiloxy)silicon 2,3-naphthalocyanines (10) were prepared via substitution of the bis(hydroxy) precursor with the corresponding chlorosilane ligands and characterized by spectroscopic and combustion analyses. They show strong absorption around 780 nm where tissues exhibit optimal transparency. Compounds 7-10 are capable of producing singlet oxygen. They are relatively photostable although less stable than the analogous phthalocyanine, i.e., the bis-(dimethylthexylsiloxy)silicon phthalocyanine (12). They were evaluated as potential photosensitizers for the photodynamic therapy (PDT) of cancer in vitro against V-79 cells and in vivo against the EMT-6 tumor in Balb/c mice. In vitro all four dyes showed limited phototoxicity combined with substantial dark toxicity. Surprisingly, in vivo (i.v., 0.1 mumol/kg, 24 h prior to the photoirradiation of the tumor with 780-nm light, 190 mW/cm2, 400 J/cm2) all dyes induced tumor regression in at least 50% of mice whereas compound 8 gave a complete tumor response in 80% of mice without apparent systemic toxicity at doses as high as 10 mumol/kg. At 24 h postinjection, compound 8 showed a favorable tumor to muscle ratio of 7, assuring minimal damage to the healthy tissue surrounding the tumor during PDT. Our data confirm the potential of silicon naphthalocyanines as far-red-shifted photosensitizers for the PDT of cancer and indicate the importance of the selection of the two axial silicon ligands for optimal photodynamic efficacy.

Biodistribution, dosimetry and metabolism of 11beta-methoxy-(17alpha,20E/Z)-[123I]iodovinylestradiol in healthy women and breast cancer patients.

UNLABELLED: The biodistribution and dosimetry of the 20E and 20Z stereoisomers of 11 beta-methoxy-(17alpha,20)-[123I]iodovinylestradiol (MIVE) were evaluated in six healthy women. Tumor uptake and metabolism of the 20Z isomer were evaluated in 13 women referred after abnormal mammography or after discovery of a suspect mass at physical examination. METHODS: The radiopharmaceuticals were prepared from their corresponding stannyl intermediates and administrated intravenously. Blood samples were drawn at different time intervals and urine was collected for up to 24 h. Metabolites were detected by radiochromatography. Tissue distribution was followed for up to 24 h by scintigraphic imaging. The dosimetry was computed according to the Medical Internal Radiation Dose scheme. RESULTS: The 20E and 20Z isomers exhibit similar biodistribution and dosimetry patterns. Chromatographic analysis of plasma samples of healthy volunteers and cancer patients, as well as in vitro plasma incubations, confirmed the in vivo stability of (20Z)-[123I]MIVE. Radioactivity was rapidly cleared from the blood by the liver and excreted through the gut, which received the highest radiation dose (0.211 mGy/MBq). The effective doses for the adult female and male phantom were 0.054 and 0.046 mSv/MBq, respectively. Among the 13 patients imaged with (20Z)-[123I]MIVE, 3 had fibrocystic disease with no focal uptake, 8 had good agreement with in vitro estrogen receptor determination and 2 were false-positive. CONCLUSION: The radiation dose after intravenous administration of 20E- or (20Z)-[123I]MIVE at imaging dose levels is within acceptable limits. There was a good correlation between uptake of (20Z)-[123I]MIVE and the presence of estrogen receptors in breast cancer patients.

High-resolution PET imaging and quantitation of pharmaceutical biodistributions in a small animal using avalanche photodiode detectors.

UNLABELLED: The feasibility of high-resolution PET using BGO-avalanche photodiode detectors for in vivo imaging and quantitation of the biodistribution of radiopharmaceuticals in small animals is demonstrated. A prototype PET camera consisting of two scanning arrays of eight EG&G C30994 solid-state scintillation detectors was used to simulate a 310-mm diameter dual-ring animal tomograph having a 130-mm port and three imaging slices, each about 3.5 mm thick. The spatial resolution (FWHM) is 3 mm or less, isotropic and uniform throughout the 120-mm diameter field of view. METHODS: Female Fischer 344/CRBL rats implanted with subcutaneous mammary adenocarcinoma tumors were injected with copper-tetrasulfophthalocyanine (CuPcS4), a potential sensitizer for the photodynamic therapy of cancer, labeled with 64Cu (T1/2 = 12.7 hr, beta +:19%). RESULTS: In spite of the low specific radioactivity of 64Cu and other inherent limitations, organs such as the liver, kidneys and the tumor could be resolved with sufficient detail for their separation and quantitation. Apart from the tumor, agreement was obtained between the biodistributions measured by PET and by scintillation counting. The discrepancy for the tumor measurement results from averaging the radioactivity over the entire tumor volume when, in fact, CuPcS4 does not completely penetrate the tumor. This incomplete penetration is noted on the PET images. CONCLUSIONS: PET based on avalanche photodiode detectors provides an accurate measurement of target organ and tumor tissue concentrations. These preliminary results demonstrate the potential of very high resolution PET for biodistribution studies in small animals.

Scintimammography with 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestrad iol: a complementary role to 99mTc-methoxyisobutyl isonitrile in the characterization of breast tumors.

UNLABELLED: The aim of this study was to investigate a possible relationship between 99mTc-methoxyisobutyl isonitrile (MIBI) uptake and the estrogen receptor (ER) status of breast tumors as determined by 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestradi ol (MIVE) scintimammography. METHODS: Thirteen patients referred for MIVE scintimammography after abnormal mammography or finding of a suspect mass on physical examination were injected intravenously with MIVE. Planar images of the breasts and axillary region were taken with both radiopharmaceuticals and compared with pathologic examination of the tumor tissue and in vitro ER quantification. RESULTS: The presence of cancerous tissue, as indicated by MIBI uptake, is a prerequisite for the accumulation of MIVE by the breast tumors. There was no statistically significant correlation between the MIBI and MIVE tumor uptake ratios. However, the latter correlate well with the presence of ER, as determined by an in vitro assay. CONCLUSION: MIVE scans add unique information concerning the tumor ER status in breast cancer patients, which could contribute to a better characterization of the tumor and aid in the selection of the most appropriate treatment protocol.

High-resolution PET imaging for in vivo monitoring of tumor response after photodynamic therapy in mice.

UNLABELLED: The aim of this study was to investigate the use of [18F]fluoro-2-deoxy-D-glucose (FDG) and a small-animal PET scanner to assess early tumor response after photodynamic therapy (PDT) in mice. PDT consists of intravenous administration of a photosensitizer that accumulates preferentially in tumor tissue, followed by local illumination of the tumor with red light. Two different photosensitizers were used: Photofrin (PII), which has been approved for clinical use, and disulfonated aluminum phthalocyanine (AIPcS), which is a second-generation drug. These drugs have been shown to induce tumor necrosis through different action mechanisms, i.e., mainly initial vascular stasis (PII) or direct tumor cell kill (AIPcS). FDG PET was used to follow both perfusion and metabolic activity in the tumor tissue. METHODS: The study was performed using a mouse model implanted with two contralateral murine mammary tumors (5 mm diameter x 2.5 mm thickness) on the back. Only one tumor was subjected to PDT, whereas the other tumor served as a control. A total of 13 mice were studied, 1 without illumination, 3 at 30 min and 3 at 2 h after PDT with both PII-PDT and AIPcS-PDT. Dynamic PET imaging of the mice, which were placed in pairs in a prostate position parallel to the transaxial planes of the Sherbrooke animal PET scanner, was performed after a bolus injection of 11 MBq (300 microCi) FDG. Blood samples were collected concurrently from 1 mouse during each study using an automated microvolumetric blood sampler. RESULTS: Analysis of the tumor time-activity curves showed that (a) scans during the first 3 min provided an estimate of tumor perfusion, as confirmed by the blood samples; (b) the tumor FDG uptake after 15 min was a direct measurement of tumor metabolism clearly demonstrating the relative efficacy of the two PDT drugs; and (c) the tumor tracer concentration in the interval 3-15 min after FDG injection is an appropriate indicator of the different mechanisms of tumor necrosis through indirect vascular stasis (PII) or direct cell kill (AIPcS). CONCLUSION: This pilot study confirmed the feasibility of using dynamic in vivo PET imaging for assessing early tumor response to PDT in mice.

Effect of cholesterol alpha and beta epoxides on cell killing and transformation.

V-79 Chinese hamster lung fibroblasts and C3H-10T1/2 mouse embryo cells were used to study the toxicity and transformation effects of the 5 alpha,6 alpha, and 5 beta,6 beta-epoxy derivatives of cholesterol. Both epoxides were found to be carcinogenic, and the transformation frequency increased with epoxide concentration and exposure time. The 5 beta,6 beta-epoxide caused a higher level of transformation than the alpha-isomer, and this is consistent with its greater toxicity.