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Disposition, pharmacokinetics, and metabolism of 14C-fotemustine in cancer patients.

The pharmacokinetics and metabolism of intravenously infused 14C-fotemustine (about 100 mg/m2) were examined in 2 cancer patients. Plasma levels of radioactivity increased to a maximum of 4.1 and 5.5 micrograms equivalents per g when the infusion stopped then declined triexponentially with mean half-lives of about 1/2, 10 and 80 h for the initial, mid and terminal phases, respectively. Plasma levels of intact drug were lower, with maximum levels of 1.1 and 2.8 micrograms/ml, and declined monophasically with a half-life of about 24 min. Plasma clearance was high (1426 and 764 ml/min) with the volume of distribution based on areas of 47.7 and 26.4 l. Most of the radioactivity was eliminated in urine (50.1 and 61.3%) over 7 days with smaller amounts in the feces (6.8 and 0.3%) and only minimal quantities (under 0.1%) as expired carbon dioxide. Metabolites of fotemustine were identified as chloroethanol and N-nitroso-1-imidazolone-ethyl-diethylphosphonate in plasma and as 1-hydantoin-ethyl-diethyl-phosphonate and acetic acid in urine.

Aged↗

A comparative study on expression of prostatic inhibin peptide, prostate acid phosphatase and prostate specific antigen in androgen independent human and rat prostate carcinoma cell lines.

Prostatic inhibin peptide (PIP), consisting of 94 amino-acid residues is synthesized and secreted by the prostate gland. Previous studies on immunohistochemical localization of PIP in primary prostatic tumor and their metastasis, have documented the value of this peptide as a tumor marker for diagnosis of prostate cancer (PCa). The present study was undertaken to compare the expression of PIP with that of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) in androgen independent human PCa cell lines (PC-3, DU-145 and TSU-Prl) by immunoperoxidase technique. The results of the study indicated that the staining for PIP was more intense than that of PSA and PAP. The PSA staining was either weakly positive (PC-3) or totally absent (TSU-Prl and DU-145) while PAP staining was intense in PC-3 and moderate in the other two human cell lines. The intense staining observed for PIP in all of the androgen independent cell lines suggests that the synthesis and secretion of PIP is not primarily dependent on androgens. Furthermore, expression of these markers in Dunning rat cultured adenocarcinoma cell lines and tumors were studied. Positive staining for all three human tumor associated antigens (PIP, PSA and PAP) cross-reacting with the Dunning rat PCa cell lines and the tumors, suggest the suitability of this model for preclinical screening of various therapeutic agents.

Acid Phosphatase↗

Suramin.

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Drug Administration Schedule↗

Dosimetric evaluation of the conformation of the multileaf collimator to irregularly shaped fields.

PURPOSE: The goal of this study was to evaluate the dosimetric characteristics of geometric MLC prescription strategies and compare them to those of conventional shielding block. METHODS AND MATERIALS: Circular fields, square fields, and 12 irregular fields for patients with cancer of the head and neck, lung, and pelvis were included in this study. All fields were shaped using the MLC and conventional blocks. A geometric criterion was defined as the amount of area discrepancy between the MLC and the prescription outline. The "least area discrepancy" (LAD) of the MLC conformation was searched by selecting the collimator angle, meanwhile keeping a preselected position along the width of the leaf into the prescribed field. Five LAD conventions were studied. These included the LAD-0, LAD-1/3, LAD-1/2, and LAD-2/3 that inserted the leaves at the 0, 1/3, 1/2, and 2/3 of the leaf end into the prescription field, respectively. In addition, the LAD optimization was applied to the transecting (TRN) approach for leaf conformation that prescribed an equal area of overblocking and underblocking under each leaf. Film dosimetry was performed in a 20 cm polystyrene phantom at 10 cm depth 100 cm from source to axis distance (SAD) for both 6 and 18 MV photons with each of the above MLC conformations and conventional blocks. The field penumbra width, defined as the mean of the separation between the 20% and 80% isodose lines along the normal of the prescription field edge, was calculated using both the MLC and conventional block film dosimetry and compared. In a similar way, the d20 is defined as the mean separation between the 20% isodose line and the prescription field edge, and the d80 is defined as the mean separation between the 80% isodose line and the prescription field edge. RESULTS: The field penumbra width for all MLC conventions was approximately 2 mm larger than that of the conventional block. However, there was a larger variation of the separation distribution in the penumbra region of the irregular fields for the MLC, which had a standard deviation of 1 mm (a factor of 5 larger than the conventional block). The dosimetry for the circular fields showed that the LAD-TRN, LAD-1/2, and LAD-1/3 approximated the conventional blocking well in terms of d20 and d80; however, no single convention produced the best conformation for both measures. The dosimetric result of the patient treatment fields was similar for all sites. The LAD-1/3, LAD-1/2, and LAD-TRN strategies conformed to within 1 to 1.5 mm of the d80 of the conventional block for both 6 MV and 18 MV, respectively. The LAD-1/2 and LAD-TRN conformations were virtually identical, although it is proven analytically that the LAD-1/2 convention has the least overall area discrepancy of all conventions. CONCLUSIONS: The five MLC conformation conventions resulted in similar dosimetric penumbrae for all field shapes studied. The LAD-1/3, LAD-TRN, and LAD-1/2 produced the more favorable approximation to conventional block. The field penumbra width, although useful for evaluating irregular field shapes, could not describe the large local variations in the penumbra along the field edge for the MLC. These local variations could be of clinical concern when they appear near vital organs. However, the variation in a local region can potentially be reduced by minimizing the jaggedness of the leaf steps in that local region. The dosimetric results were useful as guidelines for the clinicians in the evaluation and adjustment of MLC leaf positions.

Head and Neck Neoplasms↗

Clinical results of computerized tomography-based simulation with laser patient marking.

PURPOSE: Accuracy of a patient treatment portal marking device and computerized tomography (CT) simulation have been clinically tested. METHODS AND MATERIALS: A CT-based simulator has been assembled based on a commercial CT scanner. This includes visualization software and a computer-controlled laser drawing device. This laser drawing device is used to transfer the setup, central axis, and/or radiation portals from the CT simulator to the patient for appropriate patient skin marking. A protocol for clinical testing is reported. Twenty-five prospectively, sequentially accessioned patients have been analyzed. RESULTS: The simulation process can be completed in an average time of 62 min. Under many cases, the treatment portals can be designed and the patient marked in one session. Mechanical accuracy of the system was found to be within +/- 1mm. The portal projection accuracy in clinical cases is observed to be better than +/- 1.2 mm. Operating costs are equivalent to the conventional simulation process it replaces. CONCLUSION: Computed tomography simulation is a clinical accurate substitute for conventional simulation when used with an appropriate patient marking system and digitally reconstructed radiographs. Personnel time spent in CT simulation is equivalent to time in conventional simulation.

Computer Simulation↗

Dietary influences on endocrine-inflammatory interactions in prostate cancer development.

Prostate cancer is the most frequently diagnosed non-cutaneous cancer and is the second leading cause of cancer death in American men. The focus of this review is to define the relationship between hormonal (testosterone/estrogens) stimulation of chronic inflammation, generation of reactive oxygen species (ROS), and uncontrolled prostate cell proliferation, and review putative dietary chemoprevention strategies that focus on these processes. It has been proposed that elevated estrogen in men who already have high blood testosterone are at high risk for prostate cancer. We hypothesized that elevated estrogen, in the presence of testosterone, causes prolonged activation of a redox-sensitive transcription factor, nuclear factor kappa B (NF kappa B), that initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative and nitrative damage. The inflammatory cascade is proposed to link with uncontrolled proliferation through up-regulated Wnt signal and abnormal catenin accumulation in the prostate. Finally, a strategy that emphasizes a "whole food" based approach to cancer prevention by selecting food products that bear anti-inflammatory and anti-proliferative properties may be most promising as an effective dietary chemopreventive strategy.

Diet Therapy↗

Fibroblast growth factor signaling in tumorigenesis.

Fibroblast growth factors and their signaling receptors have been associated with multiple biological activities, including proliferation, differentiation and motility. Consequently, they have evoked interest as candidate oncogenes with the potential to initiate and/or promote tumorigenesis. This has resulted in a large literature describing the presence of these growth factors and their receptors in cancer cell lines and primary tumors of diverse origin. However, it is only recently that compelling evidence has emerged to implicate the fibroblast growth factors (Fgfs) and their receptors in the genesis of human cancers. Here, we outline the model systems that demonstrate the potential oncogenic nature of Fgf signaling and summarise recent evidence that implicates aberrant Fgf signaling as important in the natural history of some common human cancers.

Animals↗

Platelet-derived growth factor receptor (PDGFR): a target for anticancer therapeutics.

Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) have been implicated in the pathogenesis of a number of tumor types and play an important role in angiogenesis. Tumor growth can be promoted by PDGF via autocrine stimulation of malignant cells, by overexpression or overactivation of PDGFRs, or by stimulation of angiogenesis within the tumor. These mechanisms could provide possible therapeutic targets. PDGFR blockade may also lower the interstitial fluid pressure within solid tumors and enhance drug delivery. Here we discuss the possible therapeutic roles of PDGFR antagonists in the treatment of cancer, alone and in combination with chemotherapy or other targeted agents. Extensive experimental data highlight the potential therapeutic advantage of targeting PDGFR. However, recent clinical data suggest that antagonism of this growth factor is associated with fluid accumulation that could obscure any clinical benefit. Further clinical research is required to optimise inhibition of this cytokine-receptor system.

Angiogenesis Inhibitors↗

Intraprostatic spermatozoa: zonal distribution and association with atrophy.

Intraprostatic spermatozoa (IS) have been demonstrated in only 2 articles in the literature reporting on postmortem prostates. Intraprostatic spermatozoa have not been previously described in radical prostatectomies. This is the first study that describes the presence of IS in radical prostatectomies with prostatic carcinoma (PC) and its association with atrophy. We examined whole mount sagittal sections from 69 consecutive radical prostatectomy cases for PC. A central section including the seminal vesicle ejaculatory duct urethra complex (SVEDU) from each case was stained with Berg's stain to identify spermatozoa and their location. The extent and the type of atrophy were assessed on the entire prostate by using a grid method. Eighteen cases (26.1%) revealed spermatozoa both in the SVEDU and in the prostate (IS) (group 1). Twenty-two cases (31.9%) showed spermatozoa exclusively in the SVEDU but not in the prostate (group 2). The remaining 29 cases (42.0%) had no spermatozoa in either site. Location of IS was 72.2% peripheral zone, 22.2% central zone, and 5.6% transitional zone. Intraprostatic spermatozoa were frequently seen accompanied by inflammatory infiltrate in the periglandular stroma. The extent of atrophy was greater in group 1 than in group 2 (25.7% versus 15.3%; P = .006). Postatrophic hyperplasia was seen more frequently in group 1 than in group 2 (72.2% versus 40.9%; P = .025). In conclusion, the frequency of IS is 26.1% when including all prostates and 45.0% when including prostates with evidence of residual ejaculate (spermatozoa in the SVEDU), more than previously reported. Intraprostatic spermatozoa are predominantly located in the peripheral zone similar to atrophy and PC. Prostates with IS have larger atrophic areas and increased frequency of postatrophic hyperplasia. The role of IS in the pathogenesis of prostate inflammation and atrophy should be investigated.

Adenocarcinoma↗