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Biomedical subjects

J A Koutcher

Publications and source records attributed to J A Koutcher.

At least 19 recordsLinked to original sources
PubMed2006

In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.

The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

Biomarkers, Tumor↗
PubMed2006

Longitudinal MR spectroscopic imaging of pediatric diffuse pontine tumors to assess tumor aggression and progression.

Two pediatric patients with diffuse pontine tumors underwent MR spectroscopic imaging pre- and postradiation. Choline/creatine (Cho/Cr) and Cho/N-acetylaspartate (NAA) ratios were elevated before treatment, with no MR imaging contrast enhancement. These ratios were further elevated at 2 posttreatment follow-up studies, despite signs of excellent clinical improvement at initial follow-up. This study suggests that MR spectroscopic imaging is more specific in assessing the aggressiveness of diffuse pontine tumors than conventional MR imaging and can serve as a valuable tool in early prognostication.

Brain Stem Neoplasms↗
PubMed2005

Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma.

BACKGROUND: Magnetic resonance spectroscopy imaging (MRSI) non-invasively evaluates the metabolic profile of normal and abnormal brain tissue. Primary central nervous system lymphoma (PCNSL) is a highly aggressive tumor responsive to high-dose methotrexate based regimens. Patients often have complete responses but relapses are common. We characterized the MR spectra of PCNSL patients, correlated MRSI with MRI and evaluated whether early recurrence could be detected by MRSI. METHODS: Patients with PCNSL had multi-voxel MRSI before, during, and after treatment. The region of interest was defined using axial FLAIR images. Metabolites assessed were N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), lipid, and lactate. Ratios of Cho/Cr, NAA/Cho, and NAA/Cr were calculated and correlated with MRI. Overall survival (OS), progression free survival (PFS), and relative risks of each of the ratios were determined. RESULTS: MRSI was performed on 11 men and seven women; median age of 59. Sixty-seven MRSI studies were performed, 17 baseline and 48 follow-up studies. Median ratios in 16 pretreated patients were Cho/Cr-1.90, NAA/Cho-0.39, and NAA/Cr-1.27. Two patients had lipid at baseline, five had lactate and two had both. MRSI correlated with tumor response or progression on MRI; in three patients MRSI suggested disease progression prior to changes on MRI. Univariate analysis of metabolite ratios, lipid, and lactate revealed that none significantly affected PFS or OS. Kaplan-Meier analysis of the presence or absence of lipid, lactate or both revealed a trend for increased PFS. CONCLUSION: MRSI and MRI correlate with tumor response or progression and may allow early detection of disease recurrence. The presence or absence of lipid and/or lactate may have prognostic significance. Further research using MRSI needs to be done to validate our findings and determine the role of MRSI in PCNSL.

Adult↗
PubMed2005

Spectral and temporal near-infrared imaging of ex vivo cancerous and normal human breast tissues.

Cancerous and normal ex vivo human breast tissues were investigated using spectroscopic and time-sliced two-dimensional (2-D) transillumination imaging methods in order to demonstrate the importance and potential of spectral and temporal measurements in breast cancer detection and diagnosis. The experimental arrangement for time-sliced optical imaging used 120 fs, 1 kHz repetition-rate, 800 nm light pulses from a Ti:sapphire laser system for sample illumination, and a 80 ps resolution ultrafast gated intensified camera system for recording 2-D time-sliced images. The spectroscopic imaging arrangement used 1225-1300 nm tunable output of a Cr: forsterite laser for sample illumination, a Fourier space gate to discriminate against multiple-scattered light, and a near-infrared area camera to record 2-D images. Images recorded with earlier temporal slices of transmitted light highlighted tumors, while those recorded with later slices accentuated normal tissues. When light was tuned closer to the 1203 nm absorption resonance of adipose tissues, a marked enhancement in contrast between the images of adipose and fibrous tissues was observed. A similar wavelength-dependent difference between normal and cancerous tissues was observed. These results correlate well with pathology and nuclear magnetic resonance based analyses of the samples.

Adult↗
PubMed2004

Methodological standardization for a multi-institutional in vivo trial of localized 31P MR spectroscopy in human cancer research. In vitro and normal volunteer studies.

A multi-institutional group has been created to demonstrate the utility of in vivo 31P magnetic resonance spectroscopy (31P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of 31P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual 1H/31P tuned radiofrequency probe, quality control procedures, routine use of 1H irradiation while acquiring 31P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized 31P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting.

Biomarkers, Tumor↗
PubMed2003

In vivo multiple-mouse imaging at 1.5 T.

A multiple-mouse solenoidal MR coil was developed for in vivo imaging of up to 13 mice simultaneously to screen for tumors on a 1.5 T clinical scanner. For the coil to be effective as a screening tool, it should permit acquisition of MRIs in which orthotopic tumors with diameters >2 mm are detectable in a reasonable period of time (<1 hr magnet time) and their sizes accurately measured. Using a spin echo sequence, we demonstrated that this coil provides sufficient sensitivity for moderately high resolution images (156-176 microm in plane-resolution, 1.5 mm slice thickness). This spatial resolution permitted detection of primary brain tumors in transgenic/knockout mice and orthotopic xenografts. Brain tumor size as measured by MRI was correlated with size measured by histopathology (P < 0.001). Metastatic tumors in the mouse lung were also successfully imaged in a screening setting. The multiple mouse coil is simple in construction and may be implemented without any significant modification to the hardware or software on a clinical scanner.

Animals↗
PubMed2001

Fractionated radiation facilitates repair and functional motor recovery after spinal cord transection in rat.

Previous studies suggest that motor recovery does not occur after spinal cord injury because reactive glia abort the natural repair processes. A permanent wound gap is left in the cord and the brain-cord circuitry consequently remains broken. Single-dose x-irradiation destroys reactive glia at the damage site in transected adult rat spinal cord. The wound then heals naturally, and a partially functional brain-cord circuitry is reconstructed. Timing is crucial; cell ablation is beneficial only within the third week after injury. Data presented here point to the possibility of translating these observations into a clinical therapy for preventing the paralysis following spinal cord injury in the human. The lesion site (at low thoracic level) in severed adult rat spinal cord was treated daily, over the third week postinjury, with protocols of fractionated radiation similar to those for treating human spinal cord tumors. This resulted, as with the single-dose protocol, in wound healing and restoration of some hindquarter motor function; in addition, the beneficial outcome was augmented. Of the restored hindlimb motor functions, weight-support and posture in stance was the only obvious one. Recovery of this motor function was partial to substantial and its incidence was 100% instead of about 50% obtained with the single-dose treatment. None of the hindlimbs, however, regained frequent stepping or any weight-bearing locomotion. These data indicate that the therapeutic outcome may be further augmented by tuning the radiation parameters within the critical time-window after injury. These data also indicate that dose-fractionation is an effective strategy and better than the single-dose treatment for targeting of reactive cells that abort the natural repair, suggesting that radiation therapy could be developed into a therapeutic procedure for repairing injured spinal cord.

Animals↗
PubMed2001

Effects of Motexafin gadolinium on tumor metabolism and radiation sensitivity.

PURPOSE: Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation wherein there is enhancement of radiation efficacy. METHODS AND MATERIALS: We evaluated the effect of Gd-Tex(+2) on tumor metabolism and on tumor growth using a mouse mammary carcinoma model and (31)P nuclear magnetic resonance (NMR) experiments. Response to therapy was evaluated based on time for the tumor to regrow to pretreatment size and also tumor doubling time. RESULTS: (31)P NMR experiments indicated that Gd-Tex(+2) effected tumor energy metabolism during the first 24 hours postadministration. A decrease in phosphocreatine was noted at 2 (p < 0.04), 6 (p < 0.006), and 24 (p < 0.001) hours post Gd-Tex(+2). A decrease in nucleoside triphosphates was noted only at 2 hours (p < 0.02), with subsequent recovery at 6 hours. Phosphocreatine in control (saline treated) tumors showed a significant decrease only at 24 hours (p < 0.01). Irradiation at 2 and 6 hours post Gd-Tex(+2) induced an enhanced effect compared to radiation alone as measured by analyzing the growth curves, maximum tumor volumes, and the time for the tumors to regrow to their initial volumes. Irradiation at 24 hours post Gd-Tex(+2) induced a modest enhancement in tumor growth delay compared to radiation alone. DISCUSSION: NMR spectroscopy may be useful for monitoring tumor metabolism after treatment with Gd-Tex(+2) and administering radiation during the time of maximal efficacy of Gd-Tex(+2).

Animals↗
PubMed2001

Developments in nuclear magnetic resonance imaging and spectroscopy: application to radiation oncology.

Nuclear magnetic resonance techniques have advanced to the point where functional, physiologic, and biochemical information may be obtained from patients. Magnetic resonance imaging of tissue water can be used to measure perfusion and diffusion with submillimeter resolution. Magnetic resonance spectroscopy may be applied to the assessment of tissue metabolites that contain protons, phosphorus, fluorine, or other nuclei. The combination of imaging and spectroscopy technologies has lead to spectroscopic imaging techniques that are capable of mapping proton metabolites at resolutions as small as 0.25 cm(3) within the time constraints of a clinical imaging study. This article provides a brief review of magnetic resonance techniques for imaging of tissue physiological function and addresses possible applications in the realm of radiation oncology.

Animals↗
PubMed2001

UV reflectance spectroscopy probes DNA and protein changes in human breast tissues.

OBJECTIVE: The absorption spectrum obtained using diffuse reflectance measurements of malignant, fibroadenoma, and normal human breast tissues were studied. The spectral features in the spectrum were assigned to molecular components in the tissues. BACKGROUND DATA: Over the past decade, the methods of fluorescence, excitation, and Raman spectroscopy have been studied as potential noninvasive diagnostic tools. Useful spectroscopic information may be obtained from absorption spectra of tissues as well. However, direct measurement of absorption spectra of tissues by conventional transmission means is complicated by multiple photon scattering in tissues. Diffuse reflectance spectrum offers an indirect way to obtain absorption spectrum. METHODS: Excised malignant, fibroadenoma, and normal breast tissue samples without any treatment were obtained from pathology. Samples were placed in a quartz cuvette. The diffuse reflectance measurements between 250 nm to 650 nm were performed using an automated dual lamp spectrophotometer. The absorption spectra of breast tissues were obtained from the diffuse reflectance measurement. RESULTS: Twenty-one invasive carcinoma, 20 mixed in situ and invasive carcinoma, 14 fibroadenoma, and 39 normal breast tissue samples were studied. The absorption spectra of breast tissues were obtained from diffuse reflectance spectra. Spectral features were assigned to DNA and proteins in human breast tissue. Amplitude of changes averaged over 275 nm to 285 nm and 255 nm to 265 nm and were found to be different for malignant, fibroadenoma, and normal breast tissues. These changes arise from differences in content of protein and DNA. CONCLUSION: The peaks of absorption spectrum derived from diffuse reflectance measurements in the UV region revealed fingerprints from proteins and DNA components. The absorbance in the wavelength ranges of 275-285 nm and 255-265 nm were found to be different for malignant, fibroadenoma, and normal breast tissues. These differences provide a criterion to distinguish malignant from fibroadenoma and normal breast tissues.

Absorption↗
PubMed2001

Tumor-suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells.

Expression of neutral endopeptidase (NEP) 24.11 is diminished in metastatic, androgen-independent prostate cancers (PCs; C. N. Papandreou et al., NAT: MED:, 4: 50--57, 1998). To determine the effects on androgen-independent PC cells of overexpressing cell-surface NEP, an inducible tetracycline-regulatory gene expression system was used to stably introduce and express the NEP gene in androgen-independent TSU-Pr1 cells generating WT-5 cells, which expressed high levels of enzymatically active NEP protein when cultured in the absence of tetracycline. TN12 cells, which contain the identical vectors without the NEP gene and do not express NEP, were used as control. Expression of NEP in WT-5 cells after removal of tetracycline from the media resulted in a >80% inhibition in cell proliferation over a 1-week period (P < 0.005) compared with control cells. Tumor formation occurred in the prostate glands of orthotopically injected athymic mice killed at 30 days in 4 of 5 mice that were given injections of 2 x 10(6) WT-5 cells and were fed doxycycline (NEP suppressed), and in all mice that were given injections of TN12 cells and were fed with or without doxycycline. In contrast, only 1 of 5 mouse prostates developed a tumor in mice that were given injections of WT-5 cells and that did not receive doxycycline. Analysis of the mechanisms of NEP-induced growth suppression revealed that NEP expression in WT-5 cells induced a 4-fold increase in the number of PC cells undergoing apoptosis, and increased the expression of p21 tumor suppressor gene protein and the level of unphosphorylated retinoblastoma protein as determined by Western blot. Flow cytometric analysis show that induced NEP expression in WT-5 cells resulted in a G(1) cell cycle arrest. These data show that NEP can inhibit PC cell growth and tumorigenicity and suggest that NEP has potential as therapy for androgen-independent PC.

Androgens↗
PubMed2000

Use of phosphorous-31 nuclear magnetic resonance spectroscopy to determine safe timing of chemotherapy after hepatic resection.

Liver resection induces accelerated growth of residual hepatic micrometastases. Adjuvant chemotherapy may improve outcome if administered early after resection but may prove lethal if initiated prior to completion of DNA synthesis in regenerating liver. This study investigates phosphorus-31 nuclear magnetic resonance ((31)P-NMR) as a noninvasive tool for measuring energy changes reflective of hepatic DNA synthesis and for predicting safe timing of chemotherapy after 70% hepatectomy. To evaluate metabolic changes in regenerating liver, quantitative three-dimensional (31)P-NMR was performed, using the technique of chemical shift imaging at various time points after 70% hepatectomy in adult male Fischer rats. Animals receiving a course of 2'-deoxy-5-fluorouridine (FUDR; 100 mg/kg, i.p. four times per day x 5), initiated at the time of operation, were also evaluated to observe the effects of chemotherapy on liver regeneration. Forty-eight hours after resection, hepatic nucleoside triphosphate (NTP), which reflects ATP content, fell 37% (P < 0.03) in animals undergoing hepatectomy alone. By contrast, animals receiving FUDR after hepatectomy demonstrated a mitigated NTP response, with a drop of only 17% (P = not significant), suggesting that interruption of DNA synthesis leads to a reduced consumption of ATP. Direct measures of DNA synthesis and nuclear proliferation were correlated with NMR findings. [(3)H]Thymidine incorporation and Ki67 immunohistochemistry were performed on liver samples from rats undergoing 70% hepatectomy with and without FUDR. Both [(3)H]thymidine incorporation and Ki67 expression were inhibited significantly at 48 h in animals receiving hepatectomy and FUDR, compared with those not treated with FUDR. To determine whether NMR changes could be used to identify safe timing of chemotherapy after hepatectomy, rats were treated with a 5-day course of FUDR initiated either prior to or after NMR changes normalized. Animals treated with FUDR at the point of NTP normalization (72 h) showed significantly improved survival over those that began treatment at operation (75 % versus 17 %; P = 0.0005, log rank test). FUDR inhibits hepatic DNA synthesis and influences mortality if administered too early after hepatectomy. Chemical shift imaging is a noninvasive tool that can identify metabolic changes coinciding with DNA synthesis and nuclear proliferation after hepatectomy. (31)P-NMR may be useful for determining safe timing of chemotherapy after liver resection.

Animals↗
PubMed2000

Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging.

PURPOSE: Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. METHODS: MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. RESULTS: The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using (125)I seeds. The preset dose bounds of 100-150% to the prostate and 100-120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. CONCLUSIONS: Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for (125)I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

Algorithms↗
PubMed2000

Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality.

PURPOSE: The goals of this study were to survey and summarize the advances in imaging that have potential applications in radiation oncology, and to explore the concept of integrating physical and biological conformality in multidimensional conformal radiotherapy (MD-CRT). METHODS AND MATERIALS: The advances in three-dimensional conformal radiotherapy (3D-CRT) have greatly improved the physical conformality of treatment planning and delivery. The development of intensity-modulated radiotherapy (IMRT) has provided the "dose painting" or "dose sculpting" ability to further customize the delivered dose distribution. The improved capabilities of nuclear magnetic resonance imaging and spectroscopy, and of positron emission tomography, are beginning to provide physiological and functional information about the tumor and its surroundings. In addition, molecular imaging promises to reveal tumor biology at the genotype and phenotype level. These developments converge to provide significant opportunities for enhancing the success of radiotherapy. RESULTS: The ability of IMRT to deliver nonuniform dose patterns by design brings to fore the question of how to "dose paint" and "dose sculpt", leading to the suggestion that "biological" images may be of assistance. In contrast to the conventional radiological images that primarily provide anatomical information, biological images reveal metabolic, functional, physiological, genotypic, and phenotypic data. Important for radiotherapy, the new and noninvasive imaging methods may yield three-dimensional radiobiological information. Studies are urgently needed to identify genotypes and phenotypes that affect radiosensitivity, and to devise methods to image them noninvasively. Incremental to the concept of gross, clinical, and planning target volumes (GTV, CTV, and PTV), we propose the concept of "biological target volume" (BTV) and hypothesize that BTV can be derived from biological images and that their use may incrementally improve target delineation and dose delivery. We emphasize, however, that much basic research and clinical studies are needed before this potential can be realized. CONCLUSIONS: Whereas IMRT may have initiated the beginning of the end relative to physical conformality in radiotherapy, biological imaging may launch the beginning of a new era of biological conformality. In combination, these approaches constitute MD-CRT that may further improve the efficacy of cancer radiotherapy in the new millennium.

Fluorodeoxyglucose F18↗
PubMed2000

A quantitative assessment of liver metabolites during jaundice using three dimensional phosphorus chemical shift imaging.

Phosphorus metabolites in the jaundiced rat liver were studied by three-dimensional phosphorus chemical shift imaging (CSI). Animals were studied at 1, 2, and 3 weeks post-ligation of the common bile duct. Quantitation of metabolites was performed using an external standard. Metabolite T(1) values were assessed in CSI experiments on normal untreated animals. High-performance liquid chromatography (HPLC) was used to measure adenine nucleotides in a separate group of jaundiced rats. 3D-CSI did not detect significant changes in NTP in jaundiced animals relative to baseline controls. At two and three weeks post bile duct ligation, pH was significantly elevated. HPLC data comparing ATP levels to baseline controls also detected no change except for elevated ATP detected on Day 21. (31)P NMR chemical shift imaging may be used to assess liver metabolites under conditions of stress such as jaundice. However, absolute quantitation requires careful attention to many factors including point spread function, correct T(1) values, and adequate signal-to-noise ratio.

Adenosine Triphosphate↗
PubMed2000

The in vivo effect of bryostatin-1 on paclitaxel-induced tumor growth, mitotic entry, and blood flow.

Pretreatment of tumor cells with the protein kinase C (PKC) inhibitor bryostatin-1 enhances the cytotoxicity of most chemotherapeutic agents. However, in the case of paclitaxel, this effect has been shown in vitro to be best achieved when bryostatin-1 follows (rather than precedes) paclitaxel treatment. With combination trials of bryostatin-1 and paclitaxel planned for clinical trials and with only in vitro data available regarding drug sequence, we elected to undertake an in vivo study evaluating the effect of sequential bryostatin-1 and paclitaxel in a tumor-bearing mouse model and to correlate this effect to cell cycle events, tumor metabolism, and tumor blood flow. At the maximum tolerated i.p. dose, bryostatin-1 at 80 microg/kg resulted in a small but significant increase in tumor doubling time (4.2 +/- 0.3 days) compared with control tumors (3.0 +/- 0.3 days; P < 0.01). Mice treated with i.v. paclitaxel, administered at a dose of 12 mg/kg every 12 h for three doses, weekly for 3 weeks, had a tumor doubling time of 23.4 +/- 1.7 days. Mice pretreated with i.p. bryostatin-1 (80 microg/kg) followed 12 h later by i.v. paclitaxel (12 mg/kg every 12h for three doses) weekly for 3 weeks had a tumor doubling time of 9.7 +/- 1.1 days. This was significantly less (P < .001) than paclitaxel alone, which indicated an inhibitory effect by bryostatin-1 on paclitaxel therapy. In comparison, tumor-bearing mice that were treated with the same dose but with the sequence of paclitaxel followed by bryostatin-1 had a tumor doubling time of 29.6 +/- 0.6 days. This was significantly greater than the tumor doubling times for any condition tested (P < 0.01), demonstrating the sequence dependence of this combination. The efficacy of paclitaxel is dependent on mitotic entry, a step that requires activation of p34cdc2 kinase activity. Treatment with paclitaxel in vivo increased p34 cdc2 kinase activity in the mouse mammary tumors, whereas administration of bryostatin-1 before paclitaxel prevented the p34cdc2 kinase activation by paclitaxel. This was further evaluated in vitro by flow cytometry in MKN-74 human gastric cancer cells. As determined by MPM-2 labeling, which identifies cells in mitosis, pretreatment with bryostatin-1 prevented paclitaxel-treated cells from entering mitosis. Bryostatin-1 has been reported to induce changes in muscle metabolism and to decrease muscle blood flow. These events could impact on the interaction of bryostatin-1 with paclitaxel. Using proton-decoupled phosphorus nuclear magnetic resonance (31P-NMR) spectroscopy in vivo, bryostatin-1 at 80 micro1g/kg induced a decrease in both intratumoral pH and high-energy phosphates. In vivo perfusion studies, using dynamic enhanced NMR imaging with gadolinium diethylenetriamine pentaacetic acid, also demonstrated decreased tumor blood flow. These studies suggest that the inhibition of tumor response to paclitaxel by bryostatin-1 is multifactorial and includes such diverse factors as inhibition of cell entry into mitosis, a decrease in pH and energy metabolism, and a decrease in tumor blood flow. These results indicate that, as this combination enters Phase I clinical trials, the sequence of paclitaxel followed by bryostatin-1 will be critical in the clinical trial design.

Animals↗
PubMed2000

Magnetic resonance spectroscopic studies of the prostate.

Since the first suggested use of nuclear magnetic resonance (NMR) for detecting cancer, followed by the demonstration of the feasibility of imaging based on the NMR signal in 1973, magnetic resonance imaging (MRI) has become the modality of choice for a variety of clinical applications. Subsequently, the use of NMR spectroscopy (MRS) to detect the presence of different metabolites in vivo has provided unique opportunities for obtaining physiological and biochemical information. More recently, improvements in NMR equipment (magnet, electronics, computers, gradients coils, radiofrequency coils) and pulse sequences (software) have further improved these capabilities. The distinctions between MRI and MRS have begun to blur as new techniques emerge that combine imaging and spectroscopy, generating MRS images of a variety of metabolites. This review provides a brief overview of recent developments in MRS studies pertinent to the clinical evaluation of prostate cancer. The paper has been divided into three parts: a brief qualitative theoretical section about MRS, a review of in vitro studies, and a discussion of the clinical studies of the human prostate.

Adenocarcinoma↗