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J V Moore

Publications and source records attributed to J V Moore.

At least 55 records · Page 3Linked to original sources

In situ comparison of 665 nm and 633 nm wavelength light penetration in the human prostate gland.

The depth of treatment in photodynamic therapy (PDT) of tumors varies with the wavelength of light activating the photosensitizer. New generation photosensitizers that are excited at longer wavelengths have the potential for increasing treatment depths. Tin ethyl etiopurpurin (SnET2), a promising second-generation photosensitizer is maximally activated at 665 nm, which may be significantly more penetrating than 633 nm light currently used with porphyrins in PDT. The penetration of 665 nm and 633 nm wavelength red light in the prostate gland was compared in 11 patients undergoing prostatic biopsies for suspected prostatic cancer. Interstitial optical fibers determined the light attenuation within the prostate gland. Of the 11 patients, 7 had dual wavelength and 4 had single wavelength studies. The mean attenuation coefficients, mueff, for 665 nm and 633 nm wavelength light were 0.32 +/- 0.05 mm-1 and 0.39 +/- 0.05 mm-1, respectively, showing a statistically significant difference (P = 0.0003). This represented a 22% increase in the mean penetration depth and at 10 mm from the delivery fiber there was 1.8 times as much 665 nm light fluence than 633 nm. The mean mueff at 665 nm for benign and malignant prostate tissue were similar (P = 0.42), however, there was significant interpatient variation (mueff ranging from 0.24 to 0.42 mm-1) reflecting biological differences of therapeutic importance. The enhanced light fluence and penetration depth with 665 nm light should allow significantly larger volumes of prostatic tissue to be treated with SnET2-mediated PDT.

Humans↗

In vivo laser light distribution in human prostatic carcinoma.

The extent of laser light diffusion within prostatic tumor is of major importance in the treatment of localized prostatic cancer with photodynamic therapy (PDT). The penetration of 633 nm. wavelength red light was studied in eleven patients with suspected prostatic cancer using a novel method suitable for in situ measurements. Light delivery and detector fiber, placed interstitially within the gland, determined light attenuation at different interfiber separations. Of 11 patients, 10 had bilateral and 1 had single lobe studies. The mean +/- the standard error of the mean attenuation coefficients (sigma eff) for benign and malignant prostate tissue were 0.35 +/- 0.02 mm-1 and 0.36 +/- 0.02 mm-1, respectively, indicating similar optical densities (p = .58). Patients with bilateral lobe involvement showed little intraglandular variation in sigma eff (p = 0.23). However, there was interpatient variation (sigma eff = 0.28 to 0.48 mm-1) reflecting biological differences which, though therapeutically important, were not statistically significant (p = 0.057). This study showed that treatment requires individualization and predicted that 4 cylindrical diffusers are expected to destroy 25 ml. of prostatic tumor with PDT.

Humans↗

The effects of low-level direct current therapy on a preclinical mammary carcinoma: tumour regression and systemic biochemical sequelae.

Low-level direct electric current has been shown to be capable of destroying tumour tissue. Using an early-passage subcutaneous murine mammary carcinoma, the relationships between the volume of tumour destruction, charge and polarity have been examined. The results revealed a direct correlation between charge passed and absolute volume regression when the intratumoral electrode was made either an anode or a cathode. Tumour destruction for a given charge was significantly greater following anodic than cathodic treatment. A direct correlation was also observed between the percentage volume of prompt treatment-induced regression and the in situ end point of tumour growth delay. During the course of these experiments, a highly reproducible toxic effect was discovered, which has not been previously reported for this modality. An anodic charge greater than 10.6 coulombs or a cathodic charge greater than 21.6 coulombs resulted in 100% mortality at 24-72 h, while lower charges had no influence on mortality. Quantitative assays of a number of blood parameters showed that mortality was associated with serum electrolyte imbalances and appeared to be the result of the metabolic load of tumour breakdown products. These effects are similar to the tumour lysis or surgical crush syndromes and should not constitute a significant problem in clinical practice, where the tumour mass to total body mass ratio will normally be much smaller.

Animals↗

Optimization of multifiber light delivery for the photodynamic therapy of localized prostate cancer.

The understanding of light distribution within the target organ is essential in ensuring efficacy and safety in photodynamic therapy (PDT). A computer simulator of light distribution in prostatic tissue was employed for optimizing dosimetry for PDT in localized prostatic cancer. The program was based on empirically determined light distributions and optical constants and an assumed fluence rate differential from fiber source to necrosis periphery. The diffusion theory approximation to the Boltzmann transport equation was the applicable formulation relevant to prostatic tissue, which has a high albedo with forward-scattering characteristics. Solving this equation of diffusive transfer for the appropriate fiber geometry yielded the energy fluence distributions for cleaved fiber and cylindrical diffuser light delivery. These distributions, confirmed by our measurements, show a 1/r and 1/square root of r dependency (r = distance from light source) of the fluence phi (r) for the cleaved fiber and diffuser, respectively. This manifests itself by the tighter spacing of energy fluence isodoses in the case of the cleaved fiber. It was predicted that for a typical PDT regime a single interstitially placed cleaved fiber would treat 0.05-0.72 cm3. Four parallel fibers improved the uniformity of light distribution and treatment volume, and an interfiber separation of 12 mm would be necessary to provide optimal overlap of PDT necrosis, treating 0.26-3.6 cm3. The cylindrical diffuser, however, could treat larger volumes, and it was predicted that four 3 cm long diffusers at an optimal separation of 25 mm would treat 25-88 cm3 of prostatic tissue.

Computer Simulation↗

The uptake of porphyrin and zinc-metalloporphyrin by the primate prostate.

The relative distribution of sensitizer drugs in the prostate and its contiguous organs is of importance in the treatment of localized prostatic cancer with photodynamic therapy. Using the primate model, whose prostate is both morphologically and physiologically homologous with its human counterpart, the distribution of hematoporphyrin derivative (HpD) amongst organs of urological interest was determined. Hematoporphyrin derivative levels were comparatively low in both caudal and cranial prostatic lobes (0.93-1.77 micrograms/g) and were similar to those in rectum, urethra and the skin. The reticuloendothelial organs, liver, spleen and also the kidney accumulated the highest quantities of porphyrin (4.76-9.8 micrograms/g, liver > spleen > kidney). Despite a high avidity of prostatic tissue for zinc, a zinc-metalloporphyrin (Zn-HpD) did not concentrate selectively in the prostate. The results are of clinical value in view of the homology between the primate and the human.

Aging↗

Nitrogen analogues of haematoporphyrin and haematoporphyrin derivative.

The preparation of a number of amines related to haematoporphyrin (HP) and haematoporphyrin derivative (HPD) have been studied and their composition and structure discussed through examination of their 1H, 13C NMR and mass spectral data and other physical properties. In vitro biological studies have been carried out and have shown these amines to have a similar photodynamic efficiency to that of HPD. One of these showed cytotoxic properties at exceptionally low light energy levels.

Cell Survival↗

Vascular function and tissue injury in murine skin following hyperthermia and photodynamic therapy, alone and in combination.

The murine tail has been used as a model for injury to skin when hyperthermia (HT) and photodynamic therapy (PDT) using haematoporphyrin derivative, are used in combination. Skin injury by either agent alone was quantitated by the probability of tail necrosis as a function of dose of agent. 'Tolerance' doses of each modality were given and changes in skin vascular function were measured by the rate of clearance of 133Xenon. This was promptly inhibited but restored to normal by 7 days. The absolute numbers of hypodermal vessels of different sizes were measured in tail cross-sections and capillary numbers were found to be greatly reduced between 1 and 7 days, and restored to normal by 21-28 days. When a tolerance dose of PDT was followed at 1, 7, 21 and 28 days by test doses of HT, or vice versa, marked enhancements in probability of necrosis were observed when the interval was 1 or 7 days (Enhancement ratio (ER)PDT-HT = 1.5 and ERHT-PDT = 1.8). Prolonging the interval between modalities to 21-28 days spared the tissue (ERHT-PDT/21 DAYS = 1.1; ERPDT-HT/28 DAYS = 1.0). Close temporal apposition of PDT and HT, such as has been advocated to improve tumour control, may also increase injury to normal tissue through vascular effects common to both.

Animals↗

Mechanisms behind the resistance of spheroids to photodynamic treatment: a flow cytometry study.

The influence of cell heterogeneity on response to photodynamic treatment (PDT) has been investigated using the human colon adenocarcinoma line WiDr, grown as spheroids and exposed to hematoporphyrin derivative. The spheroids show a marked spheroid size-dependent resistance to PDT. Using a flow cytometer, cell sub-populations have been separated, on the basis of drug fluorescence, from single cell suspensions prepared from 500 microm diameter spheroids. Cells low in fluorescence have been shown to be resistant to PDT, have a smaller median cell volume, and be enhanced in G1-type cells. These cells also show reduced low density lipoprotein uptake. The results suggest that spheroid size-dependent resistance to PDT is related to a decreasing growth fraction with increasing spheroid size. Heterogeneity of drug uptake could be a potential limitation to clinical PDT.

Adenocarcinoma↗

Photocytotoxic efficacy of sulphonated species of aluminium phthalocyanine against cell monolayers, multicellular spheroids and in vivo tumours.

The problem of relying solely on in vitro data to predict photosensitiser efficacy was demonstrated by examining the uptake and the ability to mediate photocytotoxicity of mono-, di-, tri- and tetra-sulphonated species of chloroaluminium phthalocyanine (AlS1-4Pc) in monolayer cultures of murine Colo 26 cells and in both monolayer and spheroid cultures of human WiDr cells. Cells treated in vitro, whether in monolayer or as spheroids, with the less sulphonated derivatives, AlS1Pc and AlS2Pc, were more susceptible to photocytotoxicity than those treated with AlS3Pc, cells treated with AlS4Pc were even less susceptibile to the cytotoxic effects of light irradiation. Generally these results mirrored the cellular uptake in vitro. When WiDr spheroids were increased in size from 250 microns to 500 microns there was a reduction in uptake of AlS1Pc and AlS2Pc which was reflected by the decreased sensitivity of the larger spheroids to the effects of light irradiation. AlS1Pc had no effect against Colo 26 cells growing as s.c. tumours in syngeneic BALB/c mice; whereas AlS3Pc, AlS2Pc and AlS4Pc produced significant reductions in tumour weights 5 days post laser light irradiation. Of these, AlS2Pc had the most dramatic effect on the colony forming efficiency of tumour cells recovered 24 h after PDT. While, despite their effects on tumour size, AlS3Pc and AlS4Pc scarcely affected the subsequent viability of cells from dissociated tumours. Thus the in vitro efficacy of the sulphonated species of phthalocyanines is not necessarily predictive of their in vivo effectiveness.

Animals↗

Photodynamic therapy for localised prostatic cancer: light penetration in the human prostate gland.

We are investigating the feasibility of photodynamic therapy in the treatment of localised prostatic cancer. Of major importance in this form of treatment is the extent to which light penetrates the target organ; hence, our interest in the optical properties of the human prostate gland. We obtained three whole prostates from autopsies of patients who died of non-urological causes. Red light was launched interstitially and detector fibres measured light intensity as a function of distance from the delivery fibre end. The optical constants derived from the three prostates were almost identical and indicated that light was predominantly scattered rather than absorbed (mean absorption and scattering coefficients 0.07 +/- 0.02 mm.-1 and 0.86 +/- 0.05 mm.-1 respectively). In a comparison of the tissue penetration by four different wavelengths, 633 nm red light was found to be transmitted best. Light propagation in the heavily absorbing tissue of the human liver was 4.3 times poorer than in the prostate. Such a combination of low absorption and high scattering characteristics in prostatic tissue would enhance the effectiveness of PDT. The optical constants derived will enable "light treatment planning" in patients with prostatic cancer.

Aged↗

The effect of combined modality treatment with ionising radiation and TPPS-mediated photodynamic therapy on murine tail skin.

The effect on normal skin of combined modality treatment with 300 kV X-rays and photodynamic therapy (PDT) using the photosensitising drug meso-tetra (sulphonatophenyl) porphine (TPPS) was studied using the mouse tail necrosis assay. Prior treatment with a tolerance dose of PDT produced a significant increase in the probability of necrosis following graded doses of ionising radiation. A tolerance dose of X-rays administered prior to graded doses of PDT also produced a significant rise in the necrosis rate. TPPS appeared to have a radiosensitising effect but, as the animals were kept in subdued light, the low dose of PDT they therefore received may provide an alternative explanation. The effect of prolonging the interval between the modalities on the necrosis rate did not appear to be related to the time course of either the changes in blood flow produced by each modality, measured by xenon clearance studies or the development of the skin reaction following X-ray irradiation.

Animals↗

A comparison of the sensitivity to photodynamic treatment of endothelial and tumour cells in different proliferative states.

Bovine aorta endothelial and human colon adenocarcinoma (WiDr) cells were exposed to haematoporphyrin derivative plus light. Cell survival was determined using a [3H]thymidine incorporation and a clonogenic assay for both cell types. The endothelial cells were more sensitive to photodynamic treatment. This could be explained in terms of increased drug uptake into the endothelial cells despite there being no difference in cell volume between the cells. For both tumour and endothelial cells, exponentially growing cells were more sensitive to photodynamic treatment than plateau-phase cells. This was associated with a reduction in drug uptake into plateau-phase endothelial cells. However, there was no difference in uptake into exponentially growing and plateau-phase WiDr cells.

Animals↗

A morphometric analysis of individual cell death in bronchial carcinoids.

The incidence and morphometric characteristics of individual dead cells have been measured in 51 cases of broncho-pulmonary carcinoid tumours. In both typical and atypical carcinoids, these dead cells were distinguished by nuclei that were significantly smaller and less regular than those of 'intact' tumour parenchymal cells. The proportion of dead to all tumour cells was not significantly different for typical and atypical carcinoids (17 and 13%, respectively). For 33 of these tumours, their ploidy status had also been established. In diploid tumours, the proportion of dead cells was 18% and in aneuploid tumours 12%. The prognosis of patients with atypical carcinoids was significantly worse and such tumours were more commonly aneuploid. Thus the incidence of individual cell death does not appear to be positively associated with poor prognosis in this series. The association between 'necrosis' and poor prognosis commented on in the literature may relate more to a different form of cell death, expressed histopathologically as gross coagulative necrosis, the incidence of which is significantly higher among the atypical, aneuploid tumours.

Aneuploidy↗

The high steepness of dose-response curves for late-responding normal tissues.

Values are calculated for the parameters alpha, beta, and the number of tissue-rescuing units (TRU), which together describe the location and the steepness of dose-incidence curves for functional injury in various normal tissues. The analysis is based on a Poisson model of the distribution of surviving TRUs. The steepness of the curves for early-responding tissues has been shown previously to be compatible with values of sensitivity for the target colony-forming cells in these tissues. We now show that the steepness of curves for late responses in spinal cord, lung, and kidney is higher by a factor of up to 3 than the steepness of curves for early responses in other tissues. Although the interpretation of this higher steepness is not fully understood, this observation is likely to be of importance for radiotherapy.

Animals↗

Quantitative histological changes in murine tail skin following photodynamic therapy.

Mice were treated by an intravenous injection of 2 mg of the photosensitising drug meso-tetra (sulphonatophenyl) porphine (TPPS) and 24 h later a 2.5 cm length of their tails was exposed to visible light (photodynamic therapy, PDT). Using cross-sections from the centre of the treatment field, the absolute areas occupied by epidermis, dermis, hypodermis, tendon and bone, and also the total number and area of the blood vessels in the dermis and hypodermis, were compared between control and PDT-treated animals. There was a significant increase in the mean cross-sectional area of the epidermis, dermis and hypodermis following both 90J cm-2 (a dose expected to produce a low incidence of tail necrosis) and 180J cm-2 (expected to produce a 100% tail necrosis rate), on day 1 and day 5 following light exposure. The cross-sectional area of the vascular compartment was also significantly increased by day 5 at both dose levels. Differences were observed between the two doses when the total number of blood vessels were compared. There was a significant increase in the number of blood vessels by day 5 following 90 J cm-2 in both the dermis and hypodermis, but not following 180J cm-2. This appeared to be due to a significant increase in blood vessels with a cross-sectional area of less than 100 microns2 by day 5 at the lower dose. It is concluded that angiogenesis plays an important role in vascular recovery following PDT.

Animals↗

In vivo magnetic resonance imaging of the effects of photodynamic therapy.

Nuclear magnetic resonance (NMR) proton imaging and measurements of the parameters T1 and T2, have been carried out in vivo on the murine mammary tumour T50/80. Tumours had been treated 24 h previously by photodynamic therapy (PDT, using haematoporphyrin derivative and 630 nm laser light). Proton images clearly demarcated a high signal-intensity region on the side of the tumour closest to the incident light beam, while the parts of the tumour more remote from the beam resembled the images from untreated controls. Both T1 and T2 values were raised in the high-intensity region. This high-intensity region was shown to correspond to PDT-induced histological necrosis, the low-intensity region to histologically intact tumour. Linear regression analysis of the relationship of depth of necrosis measured histologically and 'depth of necrosis' measured from the NMR images, yielded a slope of 0.93 (r2 = 0.95).

Animals↗