Irradiation of the prostate and pelvic lymph nodes with an adaptive algorithm.

PURPOSE: The simultaneous treatment of pelvic lymph nodes and the prostate in radiotherapy for prostate cancer is complicated by the independent motion of these two target volumes. In this work, the authors study a method to adapt intensity modulated radiation therapy (IMRT) treatment plans so as to compensate for this motion by adaptively morphing the multileaf collimator apertures and adjusting the segment weights. METHODS: The study used CT images, tumor volumes, and normal tissue contours from patients treated in our institution. An IMRT treatment plan was then created using direct aperture optimization to deliver 45 Gy to the pelvic lymph nodes and 50 Gy to the prostate and seminal vesicles. The prostate target volume was then shifted in either the anterior-posterior direction or in the superior-inferior direction. The treatment plan was adapted by adjusting the aperture shapes with or without re-optimizing the segment weighting. The dose to the target volumes was then determined for the adapted plan. RESULTS: Without compensation for prostate motion, 1 cm shifts of the prostate resulted in an average decrease of 14% in D-95%. If the isocenter is simply shifted to match the prostate motion, the prostate receives the correct dose but the pelvic lymph nodes are underdosed by 14% ± 6%. The use of adaptive morphing (with or without segment weight optimization) reduces the average change in D-95% to less than 5% for both the pelvic lymph nodes and the prostate. CONCLUSIONS: Adaptive morphing with and without segment weight optimization can be used to compensate for the independent motion of the prostate and lymph nodes when combined with daily imaging or other methods to track the prostate motion. This method allows the delivery of the correct dose to both the prostate and lymph nodes with only small changes to the dose delivered to the target volumes.

Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes.

Covalent intermediates between topoisomerase I and DNA can become dead-end complexes that lead to cell death. Here, the isolation of the gene for an enzyme that can hydrolyze the bond between this protein and DNA is described. Enzyme-defective mutants of yeast are hypersensitive to treatments that increase the amount of covalent complexes, indicative of enzyme involvement in repair. The gene is conserved in eukaryotes and identifies a family of enzymes that has not been previously recognized. The presence of this gene in humans may have implications for the effectiveness of topoisomerase I poisons, such as the camptothecins, in chemotherapy.

Dosimetric equivalence of nonstandard HDR brachytherapy catheter patterns.

PURPOSE: To determine whether alternative high dose rate prostate brachytherapy catheter patterns can result in similar or improved dose distributions while providing better access and reducing trauma. MATERIALS AND METHODS: Standard prostate cancer high dose rate brachytherapy uses a regular grid of parallel needle positions to guide the catheter insertion. This geometry does not easily allow the physician to avoid piercing the critical structures near the penile bulb nor does it provide position flexibility in the case of pubic arch interference. This study used CT datasets with 3 mm slice spacing from ten previously treated patients and digitized new catheters following three hypothetical catheter patterns: conical, bi-conical, and fireworks. The conical patterns were used to accommodate a robotic delivery using a single entry point. The bi-conical and fireworks patterns were specifically designed to avoid the critical structures near the penile bulb. For each catheter distribution, a plan was optimized with the inverse planning algorithm, IPSA, and compared with the plan used for treatment. Irrelevant of catheter geometry, a plan must fulfill the RTOG-0321 dose criteria for target dose coverage (V100(Prostate) > 90%) and organ-at-risk dose sparing (V75(Bladder) < 1 cc, V75(Rectum) < 1 cc, V125(Urethra) << 1cc). RESULTS: The three nonstandard catheter patterns used 16 nonparallel, straight divergent catheters, with entry points in the perineum. Thirty plans from ten patients with prostate sizes ranging from 26 to 89 cc were optimized. All nonstandard patterns fulfilled the RTOG criteria when the clinical plan did. In some cases, the dose distribution was improved by better sparing the organs-at-risk. CONCLUSION: Alternative catheter patterns can provide the physician with additional ways to treat patients previously considered unsuited for brachytherapy treatment (pubic arch interference) and facilitate robotic guidance of catheter insertion. In addition, alternative catheter patterns may decrease toxicity by avoidance of the critical structures near the penile bulb while still fulfilling the RTOG criteria.

Characteristics of megavoltage cone-beam digital tomosynthesis.

This article reports on the image characteristics of megavoltage cone-beam digital tomosynthesis (MVCB DT). MVCB DT is an in-room imaging technique, which enables the reconstruction of several two-dimensional slices from a set of projection images acquired over an arc of 20 degrees-40 degrees. The limited angular range reduces the acquisition time and the dose delivered to the patient, but affects the image quality of the reconstructed tomograms. Image characteristics (slice thickness, shape distortion, and contrast-to-noise ratio) are studied as a function of the angular range. Potential clinical applications include patient setup and the development of breath holding techniques for gated imaging.

Health management program: factors influencing completion of therapy with high-dose interferon alfa-2b for high-risk melanoma.

The goal of the 1-year observational, multicentre, open-label study reported here was to identify factors influencing adherence to high-dose interferon alfa-2b adjuvant therapy in patients at high risk of recurrence following surgical excision of malignant melanoma. The study was carried out in 23 tertiary-care centres across Canada.The 225 patients enrolled in the study all had malignant melanoma that was surgically excised and that required adjuvant treatment with interferon alfa-2b. Of these patients, 64% were men. Mean age was 51.7 years. All patients received interferon alfa-2b treatment during a 4-week induction phase (20 MU/m(2) intravenously 5 days per week) followed by a 48-week maintenance phase (10 MU/m(2) subcutaneously 3 days per week).Oncology nurses reviewed side-effect management with the patients before the induction and maintenance phases. Patients were provided with daily diaries, comprehensive educational materials, and ongoing nursing support. Data on side effects and discontinuations were obtained from patient interviews and diaries. THE MAIN OUTCOME MEASUREMENTS WERE RELATED TO TREATMENT DISCONTINUATION: rate, timing, reason, and prevention. Of the 225 patients, 75 (33.3%) discontinued interferon during the induction phase, and 58 (25.8%) discontinued during the maintenance phase. The main reasons for discontinuation were adverse events (58%) and disease progression (26%). Patients with a daily fluid intake greater than 1.5 L were more likely to complete therapy than were those with an intake less than 1.5 L (64% vs. 36%, p < 0.0001).Of 225 patients enrolled in the interferon alfa-2b health management program, 41% completed the 1-year treatment course. Higher fluid intake (>1.5 L daily) was associated with increased adherence to therapy.

Effectiveness of a nursing support program for patients with recurrent ovarian cancer receiving pegylated liposomal doxorubicin (Caelyx/Doxil).

Pegylated liposomal doxorubicin (PLD) has become the preferred alternative for ovarian cancer patients who have failed platinum-based therapy, but side effects, such as palmar-plantar erythrodysesthesia (PPE), may lead to sub-optimal drug exposure and treatment discontinuation. A prospective Canadian multicentre open-label study evaluated the effects of a nurse-administered education and support program on treatment adherence and tolerability in 112 women with recurrent ovarian cancer. Subjects received an average of four four-week PLD cycles, the recommended number of courses required to evaluate the efficacy from PLD. Side effects were common, but 75% of patients were able to complete > 3 cycles and 59% completed > 4 cycles of PLD chemotherapy. With proactive nursing intervention, the incidence of PLD-associated grade three-four toxicities such as PPE and mucositis was substantially decreased. Nursing intervention may allow more patients to receive chemotherapy on schedule, thus reproducing the conditions of the clinical study in which the efficacy of the drug has been established.

Effect of a High-Protein Energy-Restricted Diet Combined with Resistance Training on Metabolic Profile in Older Individuals with Metabolic Impairments.

Adequate protein intake and resistance training are effective strategies to maintain muscle mass, but the effect of their combination on metabolic profile during weight loss remains to be determined in older adults. The main objective of this study was to determine the effect of a 16-week high-protein caloric restriction combined with resistance training on chronic disease risk factors in obese older individuals with metabolic impairments. A total of 26 overweight adults aged between 60 and 75 years (BMI 32.4 ± 3.9 kg/m2) with at least 2 factors of the metabolic syndrome participated in this study and were randomized into two groups: 1) high-protein caloric restriction (HP; n= 12) and 2) high-protein caloric restriction combined with dynamic-resistance training (HP+RT; n=14). Caloric intake was reduced by 500 kcal/d in all participants and protein intake equated 25-30% of total calories (~1.4 g/kg/d). Exercise training consisted of 3 session/week of resistance training on pulley machines. Outcome measures included total and trunk fat mass (FM), total and appendicular lean body mass (LBM), fasting glucose level, lipid profile and blood pressure. Our results showed that total and trunk FM (all p<0.0001) as well as fasting glucose (p<0.0001), triglycerides (p=0.002) and total cholesterol (p=0.03) levels decreased similarly in both groups. However, total (p=0.04) and appendicular (p=0.02) LBM decreased in the HP group only. Our data show that high-protein energy restriction improves health profile of obese elderly at high risk of chronic disease but needs to be combined with resistance training to maintain LBM.

Phase II study of pegylated liposomal doxorubicin HCl (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small cell lung cancer.

BACKGROUND: Despite chemotherapy and radiotherapy for small cell lung cancer (SCLC), most patients die within 2 years. Response rates for second-line chemotherapy are 15-25%, with a median survival of 5 months. Caelyx, a pegylated liposomal formulation of doxorubicin, may be better tolerated and has activity in SCLC. PATIENTS AND METHODS: Thirty-two patients were enrolled in a phase II study of intravenous Caelyx (35 mg/m2), cyclophosphamide (750 mg/m2) and vincristine (1.2 mg/m2) every 21 days as second-line therapy in SCLC for up to six cycles. RESULTS: Thirty patients were evaluable for response, with a response rate of 10%. Another two had an unconfirmed response. Stable disease (SD) for >or=2 cycles was seen in an additional 53%. Grade 3 or 4 non-hematologic toxicity was seen in 17 (55%) patients (26 [22%] cycles) and included fatigue, mucositis, plantar-palmar erythrodysesthesia, rash and neuropathy. Twelve patients required transfusions. All patients on study have now expired, with a median survival of 28 weeks (7 months). For patients with SD or partial response, median time to progression was 15 weeks. CONCLUSION: The combination of Caelyx, cyclophosphamide and vincristine, despite cyclophosphamide and Caelyx dose reductions, has modest activity in relapsed SCLC with acceptable toxicity.

[Megavoltage cone-beam CT: Recent developments and clinical applications]. / Mégavoltage cone-beam CT: récents développements et applications cliniques pour la radiothérapie conformationnelle avec modulation d'intensité.

The Megavoltage cone-beam (MV CBCT) system consists of a new a-Si flat panel adapted for MV imaging and an integrated workflow application allowing the automatic acquisition of projection images, cone-beam CT image reconstruction, CT to CBCT image registration and couch position adjustment. This provides a 3D patient anatomy volume in the actual treatment position, relative to the treatment isocenter, moments before the dose delivery, that can be tightly aligned to the planning CT, allowing verification and correction of the patient position, detection of anatomical changes and dose calculation. In this paper, we present the main advantages and performance of this MV CBCT system and summarize the different clinical applications. Examples of the image-guided treatment process from the acquisition of the MV CBCT scan to the correction of the couch position and dose delivery will be presented for spinal and lung lesions and for head and neck, and prostate cancers.

Dosimetric Comparison Between 3-Dimensional Conformal and Robotic SBRT Treatment Plans for Accelerated Partial Breast Radiotherapy.

Accelerated partial breast irradiation is an attractive alternative to conventional whole breast radiotherapy for selected patients. Recently, CyberKnife has emerged as a possible alternative to conventional techniques for accelerated partial breast irradiation. In this retrospective study, we present a dosimetric comparison between 3-dimensional conformal radiotherapy plans and CyberKnife plans using circular (Iris) and multi-leaf collimators. Nine patients who had undergone breast-conserving surgery followed by whole breast radiation were included in this retrospective study. The CyberKnife planning target volume (PTV) was defined as the lumpectomy cavity + 10 mm + 2 mm with prescription dose of 30 Gy in 5 fractions. Two sets of 3-dimensional conformal radiotherapy plans were created, one used the same definitions as described for CyberKnife and the second used the RTOG-0413 definition of the PTV: lumpectomy cavity + 15 mm + 10 mm with prescription dose of 38.5 Gy in 10 fractions. Using both PTV definitions allowed us to compare the dose delivery capabilities of each technology and to evaluate the advantage of CyberKnife tracking. For the dosimetric comparison using the same PTV margins, CyberKnife and 3-dimensional plans resulted in similar tumor coverage and dose to critical structures, with the exception of the lung V5%, which was significantly smaller for 3-dimensional conformal radiotherapy, 6.2% when compared to 39.4% for CyberKnife-Iris and 17.9% for CyberKnife-multi-leaf collimator. When the inability of 3-dimensional conformal radiotherapy to track motion is considered, the result increased to 25.6%. Both CyberKnife-Iris and CyberKnife-multi-leaf collimator plans demonstrated significantly lower average ipsilateral breast V50% (25.5% and 24.2%, respectively) than 3-dimensional conformal radiotherapy (56.2%). The CyberKnife plans were more conformal but less homogeneous than the 3-dimensional conformal radiotherapy plans. Approximately 50% shorter treatment times and 50% lower number of delivered monitor units (MU) were achievable with CyberKnife-multi-leaf collimator than with CyberKnife-Iris. The CyberKnife-multi-leaf collimator treatment times were comparable to 3-dimensional conformal radiotherapy, however, the number of MU delivered was approximately 2.5 times larger. The suitability of 10 + 2 mm margins warrants further investigation.

Palmitoylation of the glucose transporter in blood-brain barrier capillaries.

Palmitoylation of GLUT1 was investigated in brain capillaries. The glucose transporter was shown to be palmitoylated using [3H]palmitate labeling and immunoprecipitation. The labeling was sensitive to methanolic KOH or hydroxylamine hydrolysis, indicating the presence of an ester or thioester bond. The released fatty acid was analyzed by reverse-phase HPLC and was identified as [3H]palmitate. Specificity of the immunoprecipitation was assessed by competitive inhibition of anti-GLUT1 binding with a synthetic C-terminal peptide against which the antibody was raised. In vivo studies were performed using capillaries isolated from control rats, streptozotocin-induced diabetic rats and diet-induced hyperglycemic rats. Glycemia was increased 2- and 5-fold in the hyperglycemic and diabetic groups, respectively. GLUT1 expression was evaluated in the three groups by Western blot analysis. A 36% decrease in GLUT1 expression was observed in the diabetic group, while there was no significant variation in GLUT1 expression in the hyperglycemic group. Palmitoylation of GLUT1 was increased in both diet-induced hyperglycemic and diabetic groups. These results suggest that palmitoylation may be involved in the regulation of glucose transport activity in hyperglycemia.

P-glycoprotein of blood brain barrier: cross-reactivity of Mab C219 with a 190 kDa protein in bovine and rat isolated brain capillaries.

P-glycoprotein (P-gp), an active efflux pump of antitumor drugs, is strongly expressed in endothelial cells of the blood brain barrier (BBB). Two proteins (155 and 190 kDa) were detected by Western blot analysis of beef and rat capillaries with the monoclonal antibody (MAb) C219. In order to characterize the nature of these proteins, their profile of solubilization by different detergents was established and compared with that of P-gp from the CHRC5 tumoral cell line. The 155 kDa protein (p155) of capillaries and the P-gp of CHRC5 cells were well solubilized by deoxycholate and Elugent, whereas the 190 kDa kDa protein (p190) was only solubilized by sodium dodecylsulfate (SDS). Both proteins have different patterns of extraction by Triton X-114, p155 partitioning as a membrane protein, while p190 was insoluble. Deglycosylation of capillary proteins resulted in a 27-28 kDa decrease in the apparent molecular weight of p155, similar to that observed for the P-gp of CHRC5 cells, but a decrease of only 7-8 for p190. Only p155 was immunoprecipitated by MAb C219. These results suggest that only p155 is the P-gp in BBB and that MAb C219 cross-reacts with a 190 kDa MDR-unrelated glycosylated protein. Consequently, the use of this antibody, which is frequently used to detect P-gp in tumors, could be a pitfall of immunohistochemistry screening for cancer tissues and lead to false positive in the diagnosis of MDR.

Optimization of permanent 125I prostate implants using fast simulated annealing.

PURPOSE: Treatment planning of ultrasound-guided transperineal 125I permanent prostatic implants is a time-consuming task, due to the large number of seeds used and the very large number of possible source arrangements within the target volume. The goal of this work is to develop an algorithm based on fast simulated annealing allowing consistent and automatic dose distribution optimization in permanent 125I prostatic implants. METHODS AND MATERIALS: Fast simulated annealing is used to optimize the dose distribution by finding the best seed distribution through the minimization of a cost function. The cost function includes constraints on the dose at the periphery of the planned target volume and on the dose uniformity within this volume. Adjustment between peripheral dose and the dose uniformity can be achieved by varying the weight factor in the cost function. RESULTS: Fast simulated annealing algorithm finds very good seed distributions within 20,000 iterations. The computer time needed for the optimization of a typical permanent implant involving 60 seeds and 14 needles is approximately 15 min. An additional 5 min are necessary for isodose distribution computations and miscellaneous outputs. CONCLUSION: The use of fast simulated annealing allows for an efficient and rapid optimization of dose distribution. This algorithm is now routinely used at our institution in the clinical planning of 125I permanent transperineal prostate implants for early stage prostatic carcinoma.

Electronic portal imaging device detection of radioopaque markers for the evaluation of prostate position during megavoltage irradiation: a clinical study.

PURPOSE: This study was designed to assess daily prostatic apex motion relative to pelvic bone structures during megavoltage irradiation. METHODS AND MATERIALS: Radioopaque markers were implanted under ultrasound guidance near the prostatic apex of 11 patients with localized prostatic carcinoma. Patients were subsequently treated with a four field-box technique at a beam energy of 23 MV. During treatment, on-line images were obtained with an electronic portal imaging device (EPID). The marker was easily identified, even on unprocessed images, and the distance between the marker and a bony landmark was measured. Timelapse movies were also reviewed. After the completion of treatment, a transrectal ultrasound examination was performed in 8 of 11 patients, to verify the position of the marker. RESULTS: We acquired over 900 digital portal images and analyzed posterioanterior and right lateral views. The quality of portal images obtained with megavoltage irradiation was good. It was possible to evaluate pelvic bone structures even without image histogram equalization. Moreover, the radioopaque marker was easily visible on every online portal image. The review of timelapse movies showed important interfraction motion of the marker while bone structures remained stable. We measured the position of the marker for each fraction. Marker displacements up to 1.6 cm were measured between 2 consecutive days of treatment. Important marker motions were predominantly in the posteroanterior and cephalocaudal directions. In eight patients, we verified the position of the marker relative to the prostatic apex with ultrasound at the end of the treatments. The marker remained in the trapezoid zone. Intratreatment images reviewed in two cases showed no-change in marker position. Our results, obtained during the treatment courses, indicate similar or larger prostate motions than previously observed in studies that used intertreatment x-ray films and CT images. Marker implantation under transrectal ultrasound was well tolerated. CONCLUSIONS: Radioopaque marker and the use of electronic portal imaging give a direct evaluation of prostatic motion during radiation treatment. As suggested in previous studies the motions observed are predominantly in the posteroanterior and cephalocaudal directions. Therefore, prostate motion during treatment is important and must be considered especially when using conformal therapy.

Evaluation of ultrasound-based prostate localization for image-guided radiotherapy.

To evaluate the use of the ultrasound-based BAT system for daily prostate alignment. Prostate alignments using the BAT system were compared with alignments using radiographic images of implanted radiopaque markers. The latter alignments were used as a reference. The difference between the BAT and marker alignments represents the displacements that would remain if the alignments were done using ultrasonography. The inter-user variability of the contour alignment process was assessed. On the basis of the marker alignments, the initial displacement of the prostate in the AP, superoinferior, and lateral direction was -0.9 +/- 3.9, 0.1 +/- 3.9, and 0.2 +/- 3.4 mm respectively. The directed differences between the BAT and marker alignments in the respective directions were 0.2 +/- 3.7, 2.7 +/- 3.9, and 1.6 +/- 3.1 mm. The occurrence of displacements >/=5 mm was reduced by a factor of two in the AP direction after the BAT system was used. Among eight users, the average range of couch shifts due to contour alignment variability was 7, 7, and 5 mm in the antero-posterior (AP), superoinferior, and lateral direction, respectively. In our study, the BAT alignments were systematically different from the marker alignments in the superoinferior, and lateral directions. The remaining random variability of the prostate position after the ultrasound-based alignment was similar to the initial variability. However, the occurrence of displacements >/=5 mm was reduced in the AP direction. The inter-user variation of the contour alignment process was significant.

The role of electronic portal imaging in tangential breast irradiation: a prospective study.

Side effects due to irradiation of normal tissues and local failure can be associated with deviations in the patient positioning in radiation therapy. In particular, tangential breast irradiation may include normal lung tissue or even a small portion of the heart in the field. A prospective study was performed to assess the precision and the reproducibility of the tangential breast irradiation technique with the help of on-line electronic portal imaging devices (EPID). The influence of respiration on the treatment set-up was evaluated. Also, a comparison was made with simulation films to study the degree of concordance with the intended treatment. Twenty patients with early breast cancer receiving post-operative radiotherapy were entered in the study. Geometrical parameters were measured from daily on-line portal images taken for approximately 17 fractions of each tangential fields. Multiple images were also acquired (six per field) for six fractions for all patients, yielding a total of 2120 images including the simulator films. Random and systematic errors were obtained. Variations of the parameters between various fractions and within the same fraction were about 3 mm (1 SD) or less. Variation between simulation and treatment set-up was 4.3 mm or less. Large maximum deviations, reaching 22.9 mm, were observed in rare cases. This confirms the need to implement daily verification procedures and to correct deviations in the treatment set-up. The study has shown that EPID can help reaching a high accuracy in patient treatment.

Seed misplacement and stabilizing needles in transperineal permanent prostate implants.

BACKGROUND AND PURPOSE: Seed misplacement occurring in transperineal permanent implants contributes to the degradation in dose coverage. It has been suggested that needles could be used to immobilize the prostate and help reduce misplacement. This study investigates the effects of parallel stabilizing needles on seed misplacement. MATERIALS AND METHODS: A group of ten patients implanted with stabilizing needles was compared with a group of 20 patients implanted without stabilization. Measurements were performed on the displacement of individual seeds and needles. The needle measurements are: insertion angle, the ratio of post-implant over pre-implant lengths and the clustering tendency, a measure of relative misplacement among the seeds of the same needle. RESULTS: No difference was observed in seed misplacement. No difference was observed in needle insertion angle, a measure which was expected to improve with the use of stabilizing needles. CONCLUSION: None of the expected effects from the use of parallel stabilizing needles have been observed. This method of prostate contention appears to be without benefits. Seed misplacement is most pronounced along the insertion axis and is caused by friction between prostatic tissues and implantation needles. Reducing friction could be a promising alternative to prostate contention in trying to reduce misplacement.

Observation study of electronic portal images for off-line verification.

PURPOSE: The goals of this study were to evaluate the use of electronic portal imaging device (EPID) paper images as off-line verification tools and to assess the feasibility of replacing portal films by EPID printed images. MATERIALS AND METHODS: Electronic portal images were acquired using a video-based imaging system. After contrast enhancement, these images were printed and compared to portal films when prescribed, and judged about their usefulness for off-line verification. A total of 2025 images were acquired from 322 fields on 137 patients. The images were shown to eight radiation oncologists and two senior residents in radiation oncology, each one of them judging fields relevant to his (her) daily practice. The questions asked were related to the choice of important anatomical structures and the visibility of such structures, the usefulness of the printed images, the comparison with portal films and the possible replacement of such films by paper images. RESULTS: Answers to the different questions were treated as quantitative scores. For the visibility question, means and standard deviations were calculated for each individual structure, then a global score was obtained for a given treatment site. Means and standard deviations were also computed for the comparison question. Proportions and confidence intervals were used for the other questions. The results show that EPID paper images are useful for some treatment sites such as breast, thorax, prostate, abdomen, pelvis (other than rectum) and axilla. The image quality remains insufficient for some other sites such as head and neck and spine. CONCLUSION: Although global anatomical landmarks scores are good, the usefulness score is not always as high because some essential anatomical structures scores must be taken into account. There is also a strong habit factor related to acceptance of EPID printed images as verification tools. As long as they see more and more images, radiation oncologists can more easily visualize anatomical structures and are less stringent when evaluating the efficiency of EPID paper images as off-line verification tools.

Reversal of P-glycoprotein-associated multidrug resistance by ivermectin.

P-Glycoprotein (P-gp) causes a multidrug resistance (MDR) phenotype in tumour cells. In some cancers, the expression of P-gp has been correlated with low clinical response to chemotherapy and survival of patients. Previous studies have shown that certain lipophilic drugs bind to P-gp and reverse the MDR phenotype of tumour cells. In this study, we extend that list of compounds and present evidence for the capacity of a potent and clinically safe anthelmintic, ivermectin (IVM), as an MDR-reversing drug. Using a highly drug-resistant human cell line, we compared IVM with other MDR-reversing agents and showed that IVM is 4- and 9-fold more potent than cyclosporin A and verapamil, respectively. The capacity of IVM to inhibit iodoaryl-azidoprazosin photolabeling of P-gp is consistent with direct binding to P-gp. Studies showed that [3H]IVM binding to membranes from resistant cells is specific and saturable with KD and Bmax values of 10.6 nM and 19.8 pmol/mg, respectively. However, while cyclosporin A or vinblastine inhibited [3H]IVM binding to membranes from drug-resistant but not drug-sensitive cells, neither verapamil nor colchicine had any effect. Furthermore, both IVM and cyclosporin A and, to a lesser extent, verapamil also inhibited [3H]vinblastine binding to membranes from drug-resistant cells. Drug transport studies showed that [3H]IVM is a substrate for the P-gp drug efflux pump. However, it was transported less efficiently by P-gp than [3H]vinblastine. Moreover, only cyclosporin A was effective in potentiating the accumulation of [3H]IVM in drug-resistant cells. Taken together, the high efficiency of MDR reversal by IVM combined with its low toxicity are consistent with the properties of an ideal MDR-reversing agent.

High pentamidine levels associated with hypoglycemia and azotemia in a patient with Pneumocystis carinii pneumonia.

We report on a patient who presented with a Pneumocystis carinii pneumonia. Intravenous pentamidine (4 mg/kg/day) was given for 14 days without the occurrence of adverse effects. During this treatment, the mean (+/- SD) serum pentamidine trough concentration was 94 +/- 16 ng/ml. Three days later, the patient was admitted because of fever, and pentamidine (4 mg/kg/day) was again started. Fasting hypoglycemia and azotemia then occurred; the mean serum trough pentamidine level was 190 +/- 10 ng/ml during this week of treatment. We conclude that the occurrence of hypoglycemia and azotemia during pentamidine therapy may not be idiosyncrasic, but seemed associated in our patient with high levels of serum pentamidine.