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Biomedical subjects

R N Carpenter

Publications and source records attributed to R N Carpenter.

16 recordsLinked to original sources
PubMed1996

[211At]methylene blue for targeted radiotherapy of human melanoma xenografts: dose fractionation in the treatment of cutaneous tumours.

3,7-(dimethylamino) phenazathionium chloride [methylene blue (MTB)] labelled with alpha-particle emitter astatine-211 (211At) selectively accumulates in melanoma cells due to an exceptionally high affinity of MTB to melanin, and proves to be a very effective agent in targeting radiotherapy for pigmented human melanoma grown in mice. This study aimed at a selection of the most advantageous [211At]MTB dose fractionation leading to irreversible regression of the treated lesions. Nude mice bearing subcutaneous human melanoma xenografts of either highly pigmented HX118 or poorly pigmented HX34 human melanoma were treated with [211At]MTB administered intravenously. The treatment was performed using three different schedules of [211At]MTB fractionation: a single large dose, five fractions delivered sequentially every 48 h and two to five fractions given with a mean frequency of one per week. The effectiveness of [211At]MTB treatment was assessed by determination of the growth rate of cutaneous tumours and length of time between tumour implantation and killing of moribund mice. [211At]MTB applied with a mean frequency of one fraction per week appeared to be the most efficient treatment for highly pigmented HX118 melanomas. Its effectiveness was dependent on [211At]MTB activity used per fraction and the size of the cutaneous tumours at the beginning of the treatment. A total dose of [211At]MTB seemed of less importance. An irreversible regression of the lesions was achieved. Poorly pigmented cutaneous melanoma xenografts were affected most significantly by [211At]MTB applied as five fractions given every 48 h. The treatment caused a temporary inhibition of tumour growth after which the lesions regained the control growth rate. These and previous results suggest that [211At]MTB could successfully control the growth of already formed lesions of pigmented melanoma, as well as prevent metastatic spread of the tumour, provided an appropriate fractionation régime of the radiolabelled compound is employed.

Animals↗
PubMed1992

211At-methylene blue for targeted radiotherapy of human melanoma xenografts: treatment of cutaneous tumors and lymph node metastases.

The next stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labeled with 211At (alpha particle emitter) concerns the treatment of cutaneous tumors and their metastases. Fragments of two human melanoma xenografts, highly pigmented HX118 and poorly pigmented HX34, implanted s.c. into nude mice, were treated with four doses of 211At-MTB injected i.v. The growth rate of cutaneous tumors and the appearance and size of their lymph node metastases served as criteria of treatment effectiveness. 211At-MTB inhibited the growth of cutaneous tumors in a manner dependent on their pigmentation and initial size. Highly pigmented smaller melanomas were affected by 211At-MTB to a greater extent than poorly pigmented and larger ones. Growth of the smallest HX118 lesions investigated was completely inhibited for 65 days, whereas the growth inhibition of HX34 tumors of the same size lasted 7 days only. 211At-MTB exhibited similar pigmentation-dependent effects toward lymph node metastases. The size of metastatic lesions derived from HX118 xenografts never reached that in control animals during the period of observation, whereas those grown from HX34 xenografts attained control values after a 50-day delay. The results demonstrated the capacity of 211At-MTB to control the growth of cutaneous melanomas and their metastases.

Animals↗
PubMed1992

The development of A [211At]-astatinated endoradiotherapeutic drug: Part I. Localization by alpha-particle autoradiography in a murine tumor model.

Alpha-particle track autoradiography has been used to define the in vivo cellular and intracellular distribution of radioactivity from the potential high linear energy transfer endoradiotherapeutic drug, 6-[211At]-astato-2-methyl-1,4-naphthoquinol bis(diphosphate) in tumor and relevant critical normal tissues of mice bearing a transplanted murine rectal carcinoma. A strikingly selective uptake of this compound into tumor cells, particularly into specific tumor cell nuclei, has been demonstrated. Its localization in certain tumor cells appears to depend on the presence of an onco-product, in this case an alkaline phosphatase isoenzyme, which is synthesized in some tumor cells and to which the compound targets. In curable tumors, it selectively concentrates in cells which may be regarded as tumor stem cells. There is low uptake into normal cells, particularly those in bone marrow, colon, and lung, where its sequestration is mainly extranuclear.

Alkaline Phosphatase↗
PubMed1992

Object classification and acoustic imaging with active sonar.

The theoretical underpinnings of underwater acoustic classification and imaging using high-frequency active sonar are studied. All essential components of practical classification systems are incorporated in a Bayesian theoretic framework. The optimum decision rules and array processing are presented and evaluated. A systematic performance evaluation methodology is derived. New results quantify the relationship between classifier performance and object geometry, acoustic imaging, and the accuracy of a priori knowledge infused into the processor.

Algorithms↗
PubMed1990

211At-methylene blue for targeted radiotherapy of human melanoma xenografts: treatment of micrometastases.

Treatment of micrometastases of HX34 human melanoma grown as xenografts in nude mice represents an advanced stage of preclinical investigations concerning targeted radiotherapy of this neoplasm using 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB) labeled with astatine-211 (211At) (alpha-particle emitter). The therapeutic effectiveness of 211At-MTB administered i.v. was determined by a lung colony assay combined with a search for metastases to organs other than the lungs. A single dose of 211At-MTB lowered the HX34 cell surviving fraction in lungs to below 10% almost independently of the time interval between cell inoculation and radioisotope injection and of 211At-MTB radioactivity within its investigated range. Radiation dose and the time of its administration did, however, influence the size of lung colonies. In contrast, the efficacy of 211At-MTB treatment as assessed by both surviving fraction and colony size was significantly dependent on a number of HX34 cells inoculated initially into mice. These results are explained by a short range of alpha-particles emitted by 211At and a mechanism of growth of lung colonies from tumor cells circulating with blood and blocking lung capillaries. Metastases in organs other than lungs and characteristic of control animals were not found in mice treated with 211At-MTB. The high therapeutic efficacy achieved proved that 211At-MTB is a very efficient scavenger of single melanoma cells distributed through blood and micrometastases with sizes below the limit of clinical detection.

Animals↗
PubMed1989

Uptake and therapeutic effectiveness of 125I- and 211At-methylene blue for pigmented melanoma in an animal model system.

The investigations concerning a targeted radiotherapy for pigmented melanoma with a radiolabeled phenothiazine derivative, 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)], were continued using melanotic and amelanotic sublines of B16 melanoma. Two radionuclides, 125I and 211At, emitting Auger electrons and alpha particles, respectively, replaced 35S previously studied since their biological effectiveness is significantly higher. In vitro autoradiography revealed a selective accumulation of methylene blue labeled with either of the radioisotopes in pigmented melanoma cells but its absence in nonpigmented cells. Treatments with [125I]MTB and [211At]MTB were performed both in vitro and in vivo, with their effectiveness determined by lung clonogenic assay. [125I]MTB proved to be relatively ineffective when incorporated into melanosomes distributed in the cytoplasm, i.e., too far away from the genome. Conspicuous therapeutic effects were achieved with [211At]MTB for pigmented melanoma only. 211At itself did not affect either of the investigated sublines of B16 melanoma confirming once again the high affinity of methylene blue to melanin. Calculations of cumulative radiation doses from [211At]MTB deposited in melanotic melanoma tumors and pigmented normal organs which would be at a particular risk led to the conclusion that [211At]MTB could be used for a highly selective and very efficient targeted radiotherapy of pigmented melanomas without damaging normal tissues.

Animals↗
PubMed1984

Biodistribution of 6-[211At]astato-2-methyl-1,4-naphthoquinol bis(diphosphate salt) and 211At- in mice with a transplanted rectal adenocarcinoma.

6-[211At]astato-MNDP is currently being investigated as a potential high LET endoradiotherapeutic drug. Biodistribution and whole-body radiation retention studies have been carried out with 6-[211At]astato-MNDP and 211At- in a murine rectal tumour model; results indicate that the 211At-C bond in the compound is metabolically stable for at least 6 h. The Mean Biological Concentration of 6-[211At]astato-MNDP in tumour tissue ranged from 170-253% over an initial 12 h period; this was higher than that observed for the [211At]astatide anion. Conversely, the uptake of compound into radiobiologically critical organs was significantly lower.

Adenocarcinoma↗
PubMed1984

An improvement in the range resolution of ultrasonic pulse echo systems by deconvolution.

Ultrasonic pulse echo systems are often limited in range resolution by the bandwidth of the piezoelectric transducer. Significant improvements in the range resolution of such systems can be obtained by minimizing the effects of the transducer's dynamic response on the overall pulse echo process. An approach to minimize the effects of the transducer is developed from linear system and impulse response techniques. In essence, the pulse echo voltage of interest is deconvolved with a pulse echo reference voltage which is obtained from an air/water interface in the nearfield of the transducer . A computer study of the pulse echo process and the deconvolution process is presented to illustrate the nature of the improvement in range resolution for several cases of interest. Finally, experimental results are presented to illustrate the improvement using commercially available transducers.

Transducers↗
PubMed1984

Radioactive derivatives of 2-methyl-1, 4-naphthoquinol bis (diphosphate salt) as anti-cancer drugs with high LET radiations.

From the results of the alpha-particle track autoradiography, the alkaline phosphatase studies, the biodistribution investigations and the therapeutic experiments with the transplanted Franks and Hemmings (1978) adenocarcinoma of the rectum in mice, an important finding is the striking selectivity of the uptake of the compound 6-211 At-astato-2-methyl-1, 4-naphthoquinol bis (diphosphate salt), after intraperitoneal injection into the tumour cell nuclei and in many cases into the nuclei of tumour stem cells, together with negligible uptake into normal colon and narrow. The compound, 6-211 At-astato-2-methyl-1, 4-naphthoquinol bis (diphosphate salt) has been found to cure about two-thirds of the transplanted adenocarcinoma of the rectum in mice after a single intra-peritoneal injection of 3-4 microCi. This approach can be regarded as a form of metabolically-directed drug targetting on to a tumour product which is an enzyme, an alkaline phosphatase isozyme, present in the cells of some tumours. The compound is being studied further from the point of view of possible human therapeutic applications.

Alkaline Phosphatase↗
PubMed1983

alpha-Particle track autoradiography for localization of a 211At-astatinated drug.

A potential endoradiotherapeutic drug, 6-211At-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt), incorporating the alpha-emitting radio-halogen astatine-211 of half-life 7.2 h, is shown to be valuable for localization studies by means of alpha-particle track autoradiography in malignant and normal cells and tissues in the mouse with transplanted adenocarcinoma of the rectum.

Adenocarcinoma↗
PubMed1983

The in vitro selective concentration of an 125I-iodinated compound in human tumor cells.

Uptake studies of the potential endoradiotherapeutic agent, 6-125I-iodo-2-methyl-1,4-naphthoquinol bis(diammonium phosphate) have been carried out in vitro on a wide range of normal and malignant human cells. In general, for a standardized dose of 0.1 microCi/ml, the uptake of the compound into normal cells was 0.0015-0.135 pCi/cell. Uptake into malignant cells was significantly higher than normal cells; uptakes of 0.89-11.3 pCi/cell were noted for melanoma, teratoma of testis, osteosarcoma and adenocarcinoma of colon and pancreas. Comparative uptake ratios for melanoma: Chang liver cells and testicular teratoma:normal testis were 29 23, respectively. Larger uptake ratios are usually observed with higher doses.

Absorption↗
PubMed1982

6-125I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) as a potential radio-halogenated anti-cancer agent: in vitro investigations and possible clinical implications.

6-125-I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) (6-125I-iodo-MNDP) has been synthesised and studied as the prototype of a class of potential radio-halogenated anti-cancer agents. The incorporated 125I provides Auger electron radiations which behave like high LET radiations in the treatment of tumours, though the accompanying X- and gamma-radiations make an undesirable contribution to the total body dose. The in vitro experiments reported show that 6-125I-iodo-MNDP is selectively concentrated in the cells of some human malignant tumours by factor of about 15 to 20 or more in relation to the cells of normal origin studied. On the basis of dosimetric considerations and comparison with clinical treatment with tritiated methylnaphthoquinol diphosphate, practical dosage of 6-125I-iodo-MNDP is suggested and clinical indications and safety of use are discussed. The types of tumour of particular interest are inoperable cases of carcinoma of the colon, carcinoma of the pancreas, malignant melanoma and osteosarcoma. Further investigations are in progress.

Animals↗