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Biomedical subjects

A T Porter

Publications and source records attributed to A T Porter.

At least 109 records · Page 6Linked to original sources
PubMed1989

Hormonal cytoreduction in locally advanced carcinoma of the prostate treated with definitive radiotherapy: preliminary results of RTOG 83-07.

RTOG 83-07 is a Phase II randomized protocol designed to compare the efficacy and toxicity of Megestrol vs Diethylstilbestrol (DES) used as cytoreductive agents prior to and during radiotherapy. The end-points of this study include tumor clearance rate, effect on serum testosterone, local-regional control, disease-free interval, and survival. Eligible patients were those with histologically confirmed locally advanced adenocarcinoma, clinical Stage B2 and C without regional lymph node involvement, or with lymph node involvement limited to the pelvis. Patients with medical conditions potentially predisposing to cardiovascular (thromboembolic) sequelae of endocrine therapy were not eligible. Patients were stratified by clinical stage, histological grade, and nodal status and were randomized to receive either Megestrol 40 mg PO tid or Diethylstilbestrol 1 mg PO tid. The drugs were started 2 months prior to initiation of radiotherapy and were continued throughout the radiotherapy course. Radiotherapy consisted of 44 to 46 Gy, 1.8 to 2 Gy per day to the regional lymphatics followed by a boost to the prostate consisting of 20 to 25 Gy, 1.8 to 2 Gy per day to a total of 65 to 70 Gy. Serum testosterone levels were recorded throughout the treatment course. Tumor response was assessed clinically and radiographically (CT scan). From March 1983 through June 1986 a total of 203 patients were accessioned to the study; 197 were analyzable. Correlation of the incidence of drug related toxicity and treatment arm assignment revealed a significantly higher incidence of complications in the Diethylstilbestrol (DES) arm. The most prominent were the differences in the incidence of gynecomastia (55% vs 7%) and fluid retention (21% vs 6%). The incidence of thromboembolic phenomena was comparable (8% vs 5% in the Megestrol arm). Although patients on the DES arm demonstrated a significantly greater median decrease in testosterone level, correlation of the treatment assigned to the rate of tumor regression and the incidence of complete response revealed no significant difference between the arms. At 3 years only 6.5% of the evaluable patients manifested evidence of local failure. The results of the study indicate comparable efficacy (using tumor clearance as an end-point) of DES and Megestrol. While DES appears more effective in suppressing testosterone it is also associated with a higher incidence of toxicity. The cytoreduction (using either DES, Megestrol, or an alternative regimen) concept remains to be tested in a Phase III study comparing it to radiotherapy alone.

Adenocarcinoma↗
PubMed1988

Remote interstitial afterloading in cancer of the prostate: preliminary experience with the MicroSelectron.

Brachytherapy in the treatment of prostate cancer is an accepted modality. A considerable experience has been accrued using Iridium interstitial therapy. The major problem associated with this choice is that of radioprotection. We describe the first clinical use of the MicroSelectron, a remote afterloading device, in prostate brachytherapy. Twenty-six patients have now been treated using this system. Approximately 55 treatment interruptions with an average 5 hr increase in overall treatment time occurs. The initial problems associated with instituting remote afterloading to prostate brachytherapy and their solutions are discussed.

Brachytherapy↗
PubMed1988

Prostate localization for the treatment planning of prostate cancer: a comparison of two techniques.

Two methods for localizing prostatic tissue for radiotherapy treatment planning are compared. The first method, using placement of gold "seed" in the urogenital diaphragm, is shown by CT scanning to accurately mark the prostatic apex. The other technique, in use at the Cross Cancer Institute for the past 18 months, employs a more rapid, less invasive method of retrograde contrast instillation. Both techniques yield equally precise localization of the prostate for subsequent treatment planning.

Gold↗
PubMed1985

Investigation of the selectivity of hydrogen abstraction in the nonenzymatic formation of hydroxyeicosatetraenoic acids and leukotrienes by autoxidation.

The biosynthetic conversions of arachidonic acid to hydroperoxyeicosatetraenoic acids (HPETEs) and the further conversion of leukotriene epoxides are accompanied by stereoselective hydrogen abstraction from the reaction substrate. Furthermore, this hydrogen removal has always been found to occur in fixed stereochemical relationship to carbon-oxygen chiral center(s) in the substrate or product. We have used stereospecifically labeled 10-3H-substrates with 14C internal standard to investigate whether the same relationships bear in HPETE and leukotriene formation during autoxidation. After autoxidation of labeled arachidonate, both the 8(R)- and 8(S)-HPETE enantiomers (resolved as diastereomer derivatives) and the 12(RS)-HPETE were observed to retain 41-47% 3H relative to the starting material. In autoxidative formation of leukotrienes from labeled 15(S)-HPETE the four main leukotrienes, including two derived from 14,15-leukotriene A4 hydrolysis, were observed to have retained an average of 45% 3H. Primary and secondary isotope effects were found to accompany these reactions. The results prove that stereorandom hydrogen abstraction occurs in autoxidation and that the hydrogen loss bears no stereochemical relationship to chiral oxygen center(s) in the HPETE product, (8(R) or 8(S], or the 15(S)-hydroperoxy substrate. We conclude that the chiral features of the biosynthetic reactions are a reflection of enzymatic control of stereochemistry. Nonetheless, the findings of primary and secondary isotope effects in autoxidation which are similar to those observed in the analogous biosynthetic reactions suggests that, except for stereochemical control, the autoxidative and enzymatic reactions may be mechanistically similar.

Arachidonic Acids↗
PubMed1985

Investigation of the chemical conversion of hydroperoxyeicosatetraenoate to leukotriene epoxide using stereospecifically labeled arachidonic acid. Comparison with the enzymatic reaction.

A series of stereospecifically labeled polyunsaturated fatty acids were prepared by biosynthesis from [8-DR-3H]- and [8-LS-3H]stearic acids. The labeled stearic acids were synthesized by a novel scheme employing readily available alkyne and aldehyde starting materials. The stereochemical purity of the prochiral tritium labels was judged to be greater than 99%, as determined by analysis of the octadec-1-yn-8(R)- and 8(S)-ol intermediates in the synthesis. Previously, the labeled arachidonic acids were used to investigate the stereoselectivity of hydrogen abstraction in the biosynthesis of leukotriene epoxides. We have now investigated the selectivity of hydrogen abstraction in a chemical synthesis of 14,15-leukotriene (LT) A4 from mixtures of [3-14C]- and either [10-DR-3H]- or [10-LS-3H]15(S)-HPETE methyl esters. Reaction with either chirally labeled precursor led to 70-95% retention of 3H relative to 14C in the 14,15-LTA4 and 10-Z-14,15-LTA4 products after purification by high performance liquid chromatography. The 15-dienone obtained from this reaction was consistently enriched in 3H relative to 14C after isolation and purification. Evidence was obtained to indicate that the majority of the 3H in the products was retained in its original location and configuration. These results indicate that the biomimetic chemical reaction is stereo-random with respect to hydrogen loss from carbon 10 and that, in contrast to the reaction as it occurs in leukocytes and platelets, in the chemical model the reaction begins by decomposition of the hydroperoxide group, with hydrogen loss from carbon 10 occurring as a late or final step.

Arachidonic Acid↗
PubMedDate not supplied

Ytterbium-169: calculated physical properties of a new radiation source for brachytherapy.

Seeds containing radioactive Ytterbium-169 (169Yb) have recently been manufactured for possible application to brachytherapy. Ytterbium-169 emits photons with an average energy of 93 keV (excluding energies less than 10 keV), and decays with a half-life of 32 days. Analytic and Monte Carlo computations have been used to predict physical quantities useful in treatment planning and radiation protection. Analytic calculations based on the primary photon spectrum of 169Yb (excluding energies less than 10 keV) yield an air-kerma rate constant of 0.0427 cGy cm2 h-1 MBq-1, and an exposure rate constant of 1.80 R cm2 mCi-1 h-1 for this radionuclide. Calculated fmed factors are 0.922 cGy/R for soft tissue and 2.12 cGy/R for bone. The first half-value layer in lead is 0.2 mm; the first tenth-value layer is 1.6 mm. Using Monte Carlo simulations, the relative dose distributions around 169Yb seeds (Amersham, prototypes 4 and 5) are provided, and are then compared with those around an 125I seed (3M model 6702). The 169Yb seeds produce more isotropic dose distributions, and for permanent implants, can deliver it at a greater initial dose rate. A value of 1.19 cm-2 was also calculated for the specific dose constant D0, a value which is applicable to both seed types. Radiation protection is not as easily achieved for permanent implants with 169Yb because of the higher energy emissions (vs 125I). However, for temporary implants, Ytterbium-169 may prove to be a useful substitute for 192Ir or 137Cs because of its relatively lower energy emissions. It is concluded that 169Yb merits further investigation, including dosimetry, radiobiological, and clinical studies.

Brachytherapy↗
PubMedDate not supplied

Brachytherapy for prostate cancer.

Brachytherapy is one of the oldest techniques of radiation therapy for prostate cancer. However, its use has been controversial due to mixed results with older implant techniques and the availability of different treatment methods. New methods of brachytherapy based on improved technology and increased understanding of radiobiology hold promise for consistently improved results. This article describe the various methods of prostate brachytherapy and reviews the clinical results for these methods.

Brachytherapy↗
PubMedDate not supplied

Systemic bone-seeking radionuclides for palliation of painful osseous metastases: current concepts.

Bone metastases require multidisciplinary treatment, the primary goal of which is to relieve pain and improve quality of life. Among the options available, bone-seeking radioisotopes are attractive because they can treat several symptomatic metastases simultaneously. This therapy may have antitumor efficacy in addition to analgesic properties. Although the ultimate place of systemic radionuclides in the treatment of bone metastases has not been firmly established, some patients clearly benefit from these modalities.

Analgesics↗
PubMedDate not supplied

A novel hydroxamic acid compound, BMD188, demonstrates anti-prostate cancer effects by inducing apoptosis. I: In vitro studies.

BACKGROUND: Prostate cancer is the most frequently diagnosed malignancy in the Western countries. Apoptosis-targeted drug development could represent a specific and effective weapon against the disease (Tang and Porter, 32: 284-293, 1997). We previously demonstrated that the arachidonate 12-lipoxygenase and its metabolic products could function as survival factors for many solid tumors (Tang et al., Proc. Natl. Acad. Sci. USA 93: 5241-5246, 1996; Tang and Honn, J. Cell. Physiol. 172: 155-170, 1997). MATERIALS AND METHODS: In this study, we synthesized a series of novel cyclic hydroxamic acid compounds that demonstrated varying degrees of inhibitory effects on the arachidonate 12-lipoxygenase. Subsequently we studied the effects of these novel compounds on human prostate cancer cells. First, all these compounds were screened on androgen-independent PC3 adenocarcinoma cells. Second, based on the results (i.e., the LD50 values) of the primary, secondary and tertiary screening, lead compounds were determined. Third, the lead compounds were utilized to study their cytotoxic effects on various prostate cancer cells as well as several types of normal cells. Finally, the molecular nature of the cell death was thoroughly characterized and the potential mechanisms of cell death were determined. RESULTS: About 30% of the compounds screened induced a strong apoptotic death of androgen-independent prostate cancer cells, PC3, with an LD50 mostly at 10-20 microM. A lead compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was subsequently identified which inhibited the growth of PC3 cells with an LD50 at approximately 10 microM. Comparative studies indicated that BMD188 induced a more potent apoptotic response in PC3 cells than several conventional chemotherapeutic drugs. Furthermore, unlike the above drugs, BMD188 could induce 100% apoptosis in tumor cells. BMD188 also caused apoptosis of other types of prostate cancer cells including cells with multidrug resistance phenotype, independent of the androgen-dependence and p53 status. By contrast, BMD188 generally demonstrated 2-5 fold lower cytotoxicity towards several normal cell types including normal prostate epithelial cells. The growth inhibition by BMD188 was due to apoptosis induction as evidenced by DNA ladder formation, PARP [poly(ADP-ribose)polymerase] cleavage, and typical apoptotic morphology. BMD188-induced apoptosis does not depend on its inhibitory effects on lipoxygenase since target cells (i.e., PC3 and Du145) did not express the lipoxygenase mRNA and protein. In contrast, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors TPCK and TLCK as well as by caspase inhibitors DEVD and zVAD. The involvement of caspases in the apoptotic effects of BMD188 was further confirmed by the activation of caspase-3 (CPP32). In the accompanying paper, we show that BMD188 also inhibits the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into the SCID or athymic nude mice. CONCLUSION: The data presented here suggest that these novel cyclic hydroxamic acid compounds, via induction of apoptotic death, may find potential clinical applications in the treatment of human prostate cancers.

Animals↗
PubMedDate not supplied

A novel hydroxamic acid compound, BMD188, demonstrates anti-prostate cancer effects by inducing apoptosis. II: In vivo efficacy and pharmacokinetic studies.

BACKGROUND: In the preceding paper, we demonstrated that, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], a newly synthesized cyclic hydroxamic acid compound, induces potent apoptotic death of prostate cancer cells in vitro. In this project, we studied the in vivo pharmacokinetic behavior and anti-tumor efficacy of this novel compound. MATERIALS AND METHODS: A bioavailability/elimination study was first performed using radiolabeled BMD188 administered to rats through intraperitoneal (i.p.), intravenous (i.v). or oral (p.o.) routes. Based on these pharmacokinetic data as well as pilot experiments on in vivo toxicity, two sets of efficacy studies, with i.p. administered BMD188, were performed in SCID mice or athymic nude mice which had been orthotopically transplanted with Du145 human prostate cancer cells. Tumor growth rate was measured and the final tumor weights and sizes determined. Subsequently, histopathological data were obtained and tumor tissue sections were used for apoptosis (i.e., TUNEL) staining. RESULTS: The pharmacokinetic studies revealed low (approximately 8%) absorption through the p.o. route and high (approximately 70%) absorption through the i.p. route. The average plasma half life (T1/2) of BMD188 was approximately 50 h. Post-absorption, plasma elimination of radioactivity was similar to that in animals given [3H]-188 intravenously. The in vivo efficacy results indicate that i.p. administered BMD188 significantly inhibited the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into SCID or athymic nude mice. The tumor-inhibitory effect of BMD188 was due to apoptosis induction in vivo, as revealed by histological analysis as well as TUNEL staining of the tumor tissue sections. CONCLUSION: Collectively, the preceding in vitro and the current in vivo studies suggest that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.

Animals↗