High Therapeutic Ratio Research Articles

Synthesis, characterization and anticancer investigation of some novel 2,5-disubstituted-1,3-thiazol-4-(5H)-ones and 1-substituted-1H-pyrazolo[3,4-d] thiazole derivatives

Fused pyrazoles and 2,5-disubstituted thiazolinone derivatives are attractive molecules for drug design development that are widely recognized as significant biological activity exhibition scaffolds. A considerable number of them were utilized as anti-cancer medications. In this current study, hybrid molecules that exhibited kinase inhibitory activity in addition to anti-tumor properties were synthesized. Our plan was to create a series of disubstituted-1,3-thiazolinone on fused pyrazolo[3,4-d]-thiazole derivatives as efficient anti-cancer drugs with low cytotoxicity and significant biological availability properties using 2-hydroxy acetophenone thiosemicarbazene and ethyl chloroacetate to provide 2-[2-(2-hydroxy phenyl)ethylidene)hydrazinyl]-1,3-thiazole-(5H)-one (3) as the essential precursor to heterocyclization processes. Compounds (3–8) were prepared and identified using infrared, 1H, and 13C NMR spectral data. These synthesized compounds were evaluated for their in vitro cytotoxic activity against the two cancer cell lines (MCF-7 breast cancer and HepG2 liver cancer). The preliminary screening of their compounds for their anti-cancer activity revealed that compound (6) possessed the highest anti-cancer activity. It's interesting to note that these substances, when compared to the reference medicines Erlotinib and Lapatinib, respectively, significantly caused apoptosis in the HepG2 and MCF-7 cell lines using flow cytometry analysis, suggesting potentially high therapeutic ratios.

Anti-Barnacle Activities of Isothiocyanates Derived from β-Citronellol and Their Structure-Activity Relationships.

Antifouling agents with low toxicity are in high demand for sustaining marine industries and the environment. This study aimed to synthesize 15 isothiocyanates derived from β-citronellol and evaluate their antifouling activities and toxicities against cypris larvae of the barnacle Amphibalanus amphitrite. The synthesized isothiocyanates exhibited effective antifouling activities (EC50 =0.10-3.33 μg mL-1 ) with high therapeutic ratios (LC50 /EC50 >30). Four isothiocyanates with an amide or isocyano group showed great potential as effective antifouling agents (EC50 =0.10-0.32 μg mL-1 , LC50 /EC50 =104-833). The enantiomers of the isothiocyanates only slightly differed in their antifouling activities. These results may serve as a basis for further research and development of β-citronellol-derived isothiocyanates as effective low-toxic antifouling agents. To the best of our knowledge, this study is the first to report the antifouling activities of isothiocyanates derived from accessible natural products.

Focal MR-Guided High-Dose-Rate Brachytherapy for Localized Prostate Cancer: A Prospective Clinical Trial

<h3>Purpose/Objective(s)</h3> Focal therapy has gained traction in the management of localized prostate cancer (PCa) based on the promise of equivalent oncologic outcomes with minimal toxicity compared to whole gland therapy. However, 20-45% of patients have persistent/recurrent disease within the first 2-5 years after most commonly-used ablative methods (e.g., HIFU, cryotherapy). Based on brachytherapy's (BT) well-established and long track-record of efficacy for PCa, we sought to test the focal therapy hypothesis in a prospective clinical trial of MR-guided HDR for men with localized PCa. <h3>Materials/Methods</h3> This prospective trial was approved in 2016 (UHN IRB# 16-5490; NCT02918253) for patients with clinically low- and favorable intermediate-risk prostate cancer, and a conspicuous lesion on mpMRI consistent with the area of pathological involvement. The CTV was derived from the mpMRI-defined GTV plus a 7 mm isotropic expansion, with 2 mm sup/inf added for the PTV. Implant and planning were performed with an MR-only workflow, and delivery with HDR BT. Treatment consisted of two separate implants within 14 days, to a prescription dose of 33-36 Gy in 2 sessions (BED ≥ 200 Gy). Biochemical recurrence (BCR), defined as > 2ng/mL above nadir was calculated using the Kaplan Meier method. Local failure, distant metastasis (DM) and toxicity events are reported as absolute rates. <h3>Results</h3> Nineteen patients have been treated, with a median age of 73 years (range 48-84), and median follow-up of 24 months (8-63). Median PSA was 6.1 ng/mL and 17/19 patients had Grade Group 2 disease. On average, the GTV and PTV corresponded to 3.56% (1.58-12.07) and 23.16% (13.71-40.75) of the median prostatic volume (40.49 cc [25.57-97.6]). Median number of catheters was 7 (4-11). Median GTV D₉₉ and PTV D₉₅ per fraction were 23.82 Gy (18.50-31.89) and 18.71 Gy (16.01-20.64), respectively. Nine patients have undergone the 2-yr local control ascertainment; 7 with mpMRI plus biopsies, and 2 with mpMRI only. At 2-years, local control and BCR-free survival were 100%; a single BCR event has been recorded 34 months after treatment. No DM or death events have occurred. The rate of treatment-related acute and late toxicities that were graded ≥ 2 was 0%. <h3>Conclusion</h3> Focal MRI-guided HDR brachytherapy as monotherapy appears to have a high therapeutic ratio and is a promising technique for localized PCa. Further follow-up will determine the durability of outcomes with this approach and the need for collaborative randomized studies.

The Impact of Temporal Changes in Irradiated nMAG Polymer Gels on Their Applicability in Small Field Dosimetry in Radiotherapy.

As advanced radiotherapy techniques progress to deliver a high absorbed dose to the target volume while minimizing the dose to normal tissues using intensity-modulated beams, arcs or stereotactic radiosurgery, new challenges occur to assure that the high treatment dose is delivered homogeneously to the tumor. Small irradiation field sizes (≤1 cm2) that tightly conform to precise target regions and allow for the deliverance of doses with a high therapeutic ratio, are of particular interest. However, the small field dosimetry using conventional dosimeters is limited by the relative large size of the detector. Radiation-sensitive polymer gels have the potential to meet this dosimetry challenge due to their almost unlimited ability in resolving three-dimensional dose distributions of any shape and makes them unique and suitable for the evaluation of dose profiles and the verification of complex doses. In this work, dose distributions in nMAG gels that have been irradiated to different doses by applying a 6 MV FFF photon beam collimated to 1 cm2, were analyzed and the dose profiles were evaluated by applying a gamma passing rate criteria of 3%/3 mm and considering different post-irradiation time intervals between the irradiation and the gels read out process. X-ray CT and NMR imaging procedures were used for the dose evaluation. It was found that the shape and uniformity of the dose profiles were changing due to post-irradiation polymerization and gelation processes, indicating time dependent growing uniformity which was better expressed for the higher delivered doses. It was estimated that in order to obtain acceptably symmetric small field dose profiles, a longer post-irradiation time is needed for getting the full scope of the polymerization as compared with the recently recommended 24 h period between irradiation and the read out processes of the dose gels. An estimated overall uncertainty (double standard deviation, 95% confidence level) of 3.66% was achieved by applying R2 measurements (NMR read out), and a 3.81–applying X-ray CT read out for 12 Gy irradiated gels 56 h post-irradiation. An increasing tendency for the uncertainty was observed with a decreasing post-irradiation time. A gamma passing rate of 90.3% was estimated for the 12 Gy irradiated gels and, 56 h post-irradiation, the X-ray CT evaluated gels as well as a gamma passing rate of 92.7% was obtained for the NMR evaluated gels applying a 3%/3 mm passing criteria.

Evaluation of treatment response and symptom progression in 400 patients with visual snow syndrome

AimsTo gather information on useful medications to treat visual snow syndrome (VSS) as well as to validate an instrument to assess its clinical severity and the course of the disorder...

Three-dimensional image-guided combined intracavitary and interstitial high-dose-rate brachytherapy in cervical cancer: A systematic review

PurposeTo evaluate the local control and toxicities of three-dimensional image-guided combined intracavitary and interstitial (IC/IS) high-dose-rate brachytherapy (BT) in cervical cancer through a systematic review. Methods and MaterialsA systematic review of relevant studies was performed through the PubMed, Web of Science, and Cochrane Library databases through May 10, 2020. Articles reporting on IC/IS technology, volumetric doses to high-risk clinical target volume (HR-CTV) and organs at risk (OARs), tumor control and/or treatment-related side effects were identified. The key information, including the type of applicator, implantation technology, characteristics of implantation, volumetric doses, tumor control, and/or treatment-related side effects, was extracted. A probit model analysis between HR-CTV D90 and tumor local control was performed. ResultsTwelve studies encompassing 520 patients were included in the probit model between HR-CTV D90 and the local control rate. The probit model showed a significant relationship between the HR-CTV D90 value and the local control probability, p = 0.003. The prescribed dose of 85 GyEQD2,10 would in theory warrant an 87.4% (95% confidence interval 82.5%–90.5%) local control rate. ConclusionIC/IS BT is an appropriate method to achieve a high therapeutic ratio for tumors with large volumes or poor responses after external irradiation in cervical cancer. The probit model showed that the dose escalation of HR-CTV D90 was helpful to improve the local tumor control rate.

Scopuquinolone B, a new monoterpenoid dihydroquinolin-2(1H)-one isolated from the coral-derived Scopulariopsis sp. fungus

Further chemical investigation of the secondary metabolites of the fungus Scopulariopsis sp. led to the discovery of a new alkaloid, scopuquinolone B (1). The structure of compound 1 was elucidated by extensive NMR spectroscopic data, CD spectrum and analysis of its Dess-Martin oxidation derivative. Compound 1 was evaluated for antilarval settlement activity of barnacle Balanus amphitrite and showed promising antifouling activity with an EC50 value of 0.103 μM and a high therapeutic ratio of 222.

A quantitative comparison of gross tumor volumes delineated on [18F]-FDG-PET/CT scan and contrast-enhanced computed tomography scan in locally advanced head and neck carcinoma treated with Intensity Modulated Radiotherapy

&lt;p&gt;Accurate tumor diagnosis is important in highly conformal techniques such as Intensity Modulated Radiotherapy (IMRT), which aims for high therapeutic ratio. We compared Gross Tumor Volume (GTV) (primary and nodal) delineated on &lt;sup&gt;18&lt;/sup&gt;F-fluorodeoxyglucose positron emission tomography ([&lt;sup&gt;18&lt;/sup&gt;F]-FDG-PET) scan to those delineated on contrast-enhanced computed tomography (CECT) scan and its impact on staging treated by IMRT.&lt;strong&gt; &lt;/strong&gt;A total of 30 consecutive patients with locally advanced squamous cell carcinoma of head and neck were included in this study. FDG-PET and CECT scans were performed with dedicated positron emission tomography–computed tomography (PET/CT) scanner in a single session as part of radiotherapy treatment planning for IMRT. After treatment with concurrent chemoradiotherapy, all patients were followed for one year. Three out of 30 patients were excluded from the final analysis, as there was complete remission in PET/CT after neoadjuvant chemotherapy. For remaining 27 cases, the primary sites were 17 oropharynx, 2 hypopharynx, 7 larynx and 1 unknown primary with secondary neck node. PET–CT resulted in changes of CT-based staging in 25% patients (up-staged in 3 and down-staged in 4). GTV delineated on PET vs CT scan was GTV-PET (primary) of 20.15 cm&lt;sup&gt;3&lt;/sup&gt; vs GTV-CT (primary) of 18.75 cm&lt;sup&gt;3&lt;/sup&gt;, &lt;em&gt;p&lt;/em&gt; = 0.803; and GTV-PET (nodes) of 28.45 cm&lt;sup&gt;3&lt;/sup&gt; vs GTV-CT (nodes) of 21.56 cm&lt;sup&gt;3&lt;/sup&gt;, &lt;em&gt;p&lt;/em&gt; = 0.589. The mismatch between two target volumes was statistically insignificant (&lt;em&gt;p&lt;/em&gt; = 0.635 for GTV primary, &lt;em&gt;p&lt;/em&gt; = 0.187 for nodes). The mean GTV-PET outside CT for primary was 5.83 cm&lt;sup&gt;3&lt;/sup&gt;, and for node was 8.47 cm&lt;sup&gt;3&lt;/sup&gt;. Median follow-up was 12 months. One-year loco-regional control was 92%. The target delineation of GTV can be improved with functional imaging [&lt;sup&gt;18&lt;/sup&gt;F]-FDG-PET/CT.&lt;/p&gt;

Individual isotoxic radiation dose escalation based on V20 and advanced technologies benefits unresectable stage III non-small cell lung cancer patients treated with concurrent chemoradiotherapy: long term follow-up.

Under the assumption that the highest therapeutic ratio could be achieved by increasing the total tumor dose (TTD) to the limits of normal tissues, the phase I trial was conducted in patients with unresectable stage III non-small cell lung cancer treated with concurrent chemoradiotherapy, to determine the feasibility and effects of individual isotoxic radiation dose escalation based on bilateral lung V20 and advanced technologies. Consecutive eligible patients were assigned to cohorts of eight. V20 of each cohort was increased from 27% to 30%, 33%, 35%, 37%, and so on. The criterion for cessation of dose escalation was defined as ≥ 2 patients in each cohort experienced dose limiting toxicity. Isotoxic dose escalation was based on V20, functional imaging was used to improve the accuracy of radiotherapy. To test the power of escalation dose, patients with TTD over 66 Gy were assigned to the higher dose group (HD), while the others to the standard dose one (SD). In result, the recommended value of V20 was 35%. For all patients, follow-up ranged from 1 to 112 months, median overall and progression free survivals were 25.0 and 13.0 months, respectively. The 1-, 3-, 5- and 8-year overall survival (OS) rates were 72.5%, 22.5%, 17.5%, and 10.0%, respectively. Especially, the OS and local recurrence-free survival of patients in HD group were significantly longer than those in SD one (P=0.035, P=0.007, respectively) without increasing severe toxicity. Thus, individual isotoxic dose escalation based on V20 with advanced technologies was feasible and effective.

Synthesis and anticancer activity of novel 3,6-disubstituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives

The development of new antitumor agents is one of the most pressing research areas in medicinal chemistry and medicine. The importance of triazole and thiadiazole rings as scaffolds present in a wide range of therapeutic agents has been well reported and has driven the synthesis of a large number of novel antitumor agents. The presence of these heterocycles furnishes extensive synthetic possibilities due to the presence of several reaction sites. Prompted by these data we designed, synthesized and evaluated a series of novel 3,6-disubstituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives as potential anticancer agents. We emphasized in the strategy of combining two chemically different but pharmacologically compatible molecules (the 1,2,4-triazole and 1,3,4 thiadiazole) in one frame. Several of the newly synthesized 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives showed substantial cytostatic and cytotoxic antineoplastic activity invitro, while they have produced relatively low acute toxicities invivo, giving potentially high therapeutic ratios. Insilico screening has revealed several protein targets including apoptotic protease-activating factor 1 (APAF1) and tyrosine-protein kinase HCK which may be involved in the biological activities of active analogues.

New, highly potent and non-toxic, chromone inhibitors of the human breast cancer resistance protein ABCG2

Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of anticancer compounds, contributing to multidrug resistance (MDR). Inhibition of ABCG2-mediated transport is then considered a promising strategy for overcoming MDR in tumors. We recently identified a chromone derivative, namely MBL-II-141 as a selective ABCG2 inhibitor, with relevant in vivo activity. Here, we report the pharmacomodulation of MBL-II-141, with the aim of identifying key pharmacophoric elements to design more potent selective and non-toxic inhibitors. Through rational structural modifications of MBL-II-141, using simple and affordable chemistry, we obtained highly active and easily-made inhibitors of ABCG2. Among the investigated compounds, derivative 4a, was found to be 3-fold more potent than MBL-II-141. It was similarly efficient as the reference inhibitor Ko143 but with the advantage of a lower intrinsic cytotoxicity, and therefore constitutes the best ABCG2 inhibitor ever reported displaying a very high therapeutic ratio.

Synthesis and Biological Evaluation of 4-Anilino-quinazolines and -quinolines as Inhibitors of Breast Cancer Resistance Protein (ABCG2)

Chemotherapeutic treatment of cancer often fails due to overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCG2, triggering active efflux of various structurally unrelated drugs. This so-called multidrug resistance (MDR) may be reversed by selective, potent, and nontoxic inhibitors of ABCG2. As only a few potent inhibitors are known, new compounds based on a 4-substituted-2-phenylquinazoline scaffold were investigated. Substitution with hydroxy, cyano, nitro, acetamido, and fluoro led to high inhibitory activities toward ABCG2. The ability to reverse MDR of the most active compounds was confirmed in a MTT efficacy assay. Moreover, a negligibly low intrinsic cytotoxicity was found resulting in a high therapeutic ratio. Investigations of the inhibitory activity toward ABCB1 and ABCC1 yielded a high selectivity toward ABCG2 for the quinazoline compounds. Quinoline-based analogues showed lower inhibitory activity and selectivity. The study yielded a variety of promising compounds, some with superior properties compared to those of the standard inhibitor Ko143.

An Automated Treatment Plan Quality Control Tool for Intensity-Modulated Radiation Therapy Using a Voxel-Weighting Factor-Based Re-Optimization Algorithm.

Intensity-modulated radiation therapy (IMRT) currently plays an important role in radiotherapy, but its treatment plan quality can vary significantly among institutions and planners. Treatment plan quality control (QC) is a necessary component for individual clinics to ensure that patients receive treatments with high therapeutic gain ratios. The voxel-weighting factor-based plan re-optimization mechanism has been proved able to explore a larger Pareto surface (solution domain) and therefore increase the possibility of finding an optimal treatment plan. In this study, we incorporated additional modules into an in-house developed voxel weighting factor-based re-optimization algorithm, which was enhanced as a highly automated and accurate IMRT plan QC tool (TPS-QC tool). After importing an under-assessment plan, the TPS-QC tool was able to generate a QC report within 2 minutes. This QC report contains the plan quality determination as well as information supporting the determination. Finally, the IMRT plan quality can be controlled by approving quality-passed plans and replacing quality-failed plans using the TPS-QC tool. The feasibility and accuracy of the proposed TPS-QC tool were evaluated using 25 clinically approved cervical cancer patient IMRT plans and 5 manually created poor-quality IMRT plans. The results showed high consistency between the QC report quality determinations and the actual plan quality. In the 25 clinically approved cases that the TPS-QC tool identified as passed, a greater difference could be observed for dosimetric endpoints for organs at risk (OAR) than for planning target volume (PTV), implying that better dose sparing could be achieved in OAR than in PTV. In addition, the dose-volume histogram (DVH) curves of the TPS-QC tool re-optimized plans satisfied the dosimetric criteria more frequently than did the under-assessment plans. In addition, the criteria for unsatisfied dosimetric endpoints in the 5 poor-quality plans could typically be satisfied when the TPS-QC tool generated re-optimized plans without sacrificing other dosimetric endpoints. In addition to its feasibility and accuracy, the proposed TPS-QC tool is also user-friendly and easy to operate, both of which are necessary characteristics for clinical use.

Consistency of Organ Geometries during Prostate Radiotherapy with Two Different Bladder and Bowel Regimens

BackgroundThe majority of Ontario cancer centres incorporate bladder and bowel preparation protocols for the treatment of prostate cancer with radical radiotherapy. Differing methods are used to achieve a full bladder and empty rectum for planning and treatment. We compared the effects of two different bladder and bowel preparation regimens on bladder, rectum, and prostate +/− seminal vesicle geometries through a course of radiotherapy. An optimal preparation would achieve reliable spatial arrangements and a high therapeutic ratio. MethodsThis prospective longitudinal study involved 59 prostate cancer patients treated with radical radiotherapy, of which half followed cohort 1 (laxative cohort) and the other cohort 2 (consistent timing cohort) bladder and bowel preparation regimen. Participants were asked to maintain an empty rectum for both planning and daily treatment appointments in cohort 1 through a fleet enema the morning of the planning appointment, and intake milk of magnesium during daily treatments. No specific bowel preparation was provided to cohort 2 patients. Instead, their appointment times were aligned with their natural bowel habits. This information was collected through a prescreening tool before treatment booking. All cohort 1 and 2 participants were asked to drink 250 mL of water 1 hour before planning and daily treatment appointments. Cohort 2 participants who identified no pre-existing urinary conditions were also asked to drink 2 L of water within 24 hours before the planning session and to continue this during treatment trajectory unless unable to do so because of treatment-induced bladder toxicities later in the treatment. A total of 1,335 structures (bladder, rectum +/− gas, and prostate +/− seminal vesicles) were contoured on the cone beam computerized tomography scans by three radiotherapists. A stringent quality assurance process was performed to assure quality and consistency of contours. Organ volumes were measured and evaluated for consistency over time from planning to completion of radiotherapy. Data analysis included the Fischer exact test and mixed effect modelling for total and subvolumes for bladder, rectum, rectal gas, and prostate +/− seminal vesicles. ResultsBaseline total volumes for bladder ranged from 132 mL to 501 mL with means of 325 mL and 315 mL in cohorts 1 and 2, respectively. Bladder volume declined 3.6 mL per fraction and 2.4 mL per fraction in cohorts 1 and 2, respectively. The volume of the bladder structure inside the planning target volume (PTV) on simulation showed no difference by cohort (P = .095) but there was an effect of time (linear P < .0005). Baseline total volumes for rectum ranged from 19.2 mL to 106.3 mL with means of 52.0 mL and 54.7 mL in cohorts 1 and 2, respectively. The volume of the rectum inside the PTV on simulation showed no difference by cohort (P = .12) or time (P = .30) during the treatment course. Volume of gas in the rectum did not vary by cohort (P = .6) or time (P = .08). Baseline total volumes for the clinical prostate +/− seminal vesicles target ranged from 37.1 mL to 167.5 mL with means of 76.2 mL and 66.0 mL in cohorts 1 and 2, respectively. The clinical target decreased by 3% in total volume during the course of radiotherapy in both cohorts, with similar rates of the target falling outside the planned PTV structure. ConclusionsNo significant difference was found between cohorts for rectal volume, gas volume, target coverage, and rectal and bladder volumes in the PTV. Hence, patients should be offered a choice between cohort 1 and 2 bowel preparation regimens to allow for patient preference customization. Cohort 2 bladder preparation regimen was shown to be superior for consistency with slightly larger volume over time.

Feasibility of accelerated partial breast irradiation with volumetric-modulated arc therapy in elderly and frail patients.

BackgroundAccelerated partial breast irradiation (APBI) is an option for adjuvant radiotherapy according to ASTRO and ESTRO recommendations. Among the available techniques, volumetric-modulated arc therapy (VMAT) is attractive but has not been extensively studied for APBI. This study assessed its feasibility, tolerance and early oncological outcomes.MethodsWe analysed the data of nine patients (median age 74 years) with ten lesions (one bilateral cancer) treated from May 2011 to July 2012 with APBI using VMAT. The radiation oncologist delineated the surgical tumour bed, and added an 18 mm isotropic margin to obtain the planning target volume (PTV). The dose was 40 Gy prescribed in 4 Gy fractions given twice a day over five days. Patients were regularly followed for toxicities and oncological outcomes.ResultsMean PTV was 100.0 cm3 and 95 % of the PTV received a mean dose of 99.7 % of the prescribed dose. Hot spots represented 0.3 % of the PTV. 6.2 %, 1.6 % and 0.3 % of the ipsilateral lung volume received 5 Gy (V5Gy), 10 Gy (V10Gy) and 20 Gy (V20Gy), respectively. Regarding the contralateral lung, V5Gy was 0.3 %, and V10Gy and V20Gy were nil. V5Gy accounted for 3.1 % of the heart. An average 580 monitor units were delivered. No acute or late grade ≥ 2 toxicities were observed. With a median follow-up of 26 months, no relapses occurred.ConclusionIn our study, VMAT allowed optimal dosimetry with consequential high therapeutic ratio in elderly and frail patients.

Potent Antifouling Marine Dihydroquinolin-2(1H)-one-Containing Alkaloids from the Gorgonian Coral-Derived Fungus Scopulariopsis sp.

Marine biofouling has a major economic impact, especially when it occurs on ship hulls or aquaculture facilities. Since the International Maritime Organization (IMO) treaty to ban the application of organotin-based paints to ships went into effect in 2008, there is an urgent demand for the development of efficient and environmentally friendly antifouling agents. Marine microorganisms have proved to be a potential source of antifouling natural compounds. In this study, six dihydroquinolin-2-one-containing alkaloids, three monoterpenoids combined with a 4-phenyl-3,4-dihydroquinolin-2(1H)-one (1-3) and three 4-phenyl-3,4-dihydroquinolin-2(1H)-one alkaloids (4-6), were isolated from the gorgonian coral-derived fungus Scopulariopsis sp. collected in the South China Sea. These dihydroquinolin-2-one-containing alkaloids were evaluated against the larval settlement of barnacle Balanus amphitrite, and antifouling activity was detected for the first time for this class of metabolites. All of them except 6 showed strong antifouling activity. Compounds 1 and 2 were discovered to be the most promising non-toxic antilarval settlement candidates. Especially, compound 1 is the strongest antifouling compound in nature until now which showed highly potent activity with picomolar level (EC50 17.5 pM) and a very safety and high therapeutic ratio (LC50/EC50 1200). This represents an effective non-toxic, anti-larval settlement structural class of promising antifouling lead compound.

Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2.

A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations.

Dihydroisocoumarin derivatives with antifouling activities from a gorgonian-derived Eurotium sp. fungus

Five pairs of new dihydroisocoumarin enantiomers, (±)-eurotiumides A–E, and two related racemates, (±)-eurotiumides F and G, were isolated from a gorgonian-derived fungus, Eurotium sp. XS-200900E6. The enantiomeric separations for (±)-eurotiumides A–E were achieved by chiral-HPLC, and their absolute configurations were determined by ECD spectra. All of the isolated compounds are rare dihydroisocoumarin derivatives with a methoxy at C-4. (+)- And (−)-eurotiumides B and D with cis configurations of H-3/H-4 exhibited potent antifouling activities against the larval settlement of the barnacle Balanus amphitrite with the EC50 values ranging from 0.7 to 2.3 μg/mL, and displayed high therapeutic ratios (LC50/EC50 >15). The tested compounds also showed extensive antibacterial activities. It was the first report of antifouling activities for dihydroisocoumarin derivatives.

MRI Versus CT Contouring of the High-Risk CTV for HDR Intracavitary Brachytherapy of Cervical Cancer Patients: Love's Labor Lost in the Dose?

Recent comparisons between MRI- and CT-based contours of the high-risk clinical target volume (HR-CTV) of cervical cancer patients receiving HDR brachytherapy showed that CT contours tend to overestimate the width of the tumor. The extra effort and accurate tumor definition with MRI has been predicted to improve dose metrics of the HR-CTV and OARs allowing for dose escalation and a higher therapeutic ratio. This work aims to compare HR-CTV volumes contoured on MRI and CT images using multiple similarity metrics, and evaluate the effect the contours have on dosimetry from optimized HDR brachytherapy plans that follow ABS guidelines.

Motion and volume change of tumor tissue depending on patient position in liver cancer treatment with use of tomotherapy

The aim of this study was to determine the proper position for the radiation treatment of liver cancer by tomotherapy by comparing the changes in the target location and volume depending on the position (prone position and supine position). Among the patients diagnosed with hepatocellular carcinoma from January to December 2012, five patients who had a similar tumor size and location were selected as study subjects. An abdominal and chest motion control device (radiation therapy device) was used to guide free respiration while Body Fix was used to minimize the motion of the abdomen. 4DCT was conducted in both the supine and prone positions. After the CT image was obtained, the contour of the target was determined before Tomotherapy Planning System Ver. 4.2 (Tomotherapy, Inc. Madison, WI, USA) was used to complete a plan and analyze the motion of the target. A dose volume histogram was used to analyze the integral dose. When the radiation treatment was conducted in the prone position, the motion due to respiration was reduced more than in the supine position (SI direction: 1.7mm, AP direction: 0.7mm, and LR direction: 0.2mm) and the target volume was also reduced (GTV: 11.7cm3, CTV: 19.4cm3, and PTV: 14.1cm3). As a result, the dose in the PTV increased by 3.4% at the maximum, whereas the dose reduction was 27.8% (V50) for the normal tissue of a normal liver: 53% (V30) for the stomach, 75% (V25) for the right kidney, and 50% (V45) for the spinal cord. Therefore, the maximum dose was assigned to the tumor tissue and at the same time, the minimum dose was observed in the normal tissue, showing a high therapeutic ratio (TR). In liver cancer treatment using tomotherapy, motion of the target volume can be minimized when the patient is placed in the prone position, rather than in the supine position. In addition, the proper dose of radiation was assigned to the tumor tissue and the absorbed dose was lower in the normal tissue.