Comparison of the intracellular pharmacokinetics of doxorubicin and 4′-epi-doxorubicin in patients with acute leukemia

Summary A direct comparison of the intracellular pharmacokinetics of 4-epi-doxorubicin and doxorubicin was carried out in five patients with leukemia who were given weekly low doses of a combination of these drugs at 20 mg each in an i.v. injection. Blood samples were collected for 48 h after administration and the drug concentrations in leukemic cells were determined by high-performance liquid chromatography (HPLC). The intracellular peak concentrations of 4-epi-doxorubicin were higher than those of doxorubicin in all patients. The AUC for the intracellular drug concentration vs time curve was significantly higher for 4-epi-doxorubicin. The intracellular uptake and retention were also studied in vitro after incubation of isolated leukemic blast cells with the two drugs; they showed the same pattern observed in vivo. We conclude that 4-epi-doxorubicin and doxorubicin exhibit different pharmacokinetics in malignant cells. The therapeutic significance of this finding requires further evaluation.     

Studies on the pharmacodynamics and pharmacokinetics of paclitaxel(Zisu®)

Pharmacological studies demonstrated that paclitaxel (Zisu®) was very active in the inhibition of the growth of human cancer cell panel including KB cells, HCT-8, A2780, andMCF-7 cells. The IC₅₀ was as low as 0.0019, 0.0019, 0.0036 and 0.01 µ g/ml respectively. Experimental therapeutic studies indicated that paclitaxel(Zisu®) significantly inhibited the growth of melanoma B-16, Walker carcinomsarcoma and heterotransplanted human ovarian cancer in nude mice. Biochemical pharmacological studies showed that paclitaxel (Zisu®) could accelerate microtubule assembly and inhibit its deassembly; population in G₁ was decreased while the cell population in G₂+M phase was increased significantly. In addition, a polyploid cell population appeared. Pharmacokinetic studies demonstrated that the $t_{{1 \mathord{\left/ {\vphantom {1 {2\alpha }}} \right. \kern-0em} {2\alpha }}} $ was 0.12 h and $t_{{1 \mathord{\left/ {\vphantom {1 {2\beta }}} \right. \kern-0em} {2\beta }}} $ was 5.02 h when it was injected intravenously at a dose of 5 mg/kg in rats. The AUC, Vc and CLs were 11.82(µg.h)/ml, 0.50L/kg and 0.42L(h.kg) respectively.     

Effect of gastrectomy on the pharmacokinetics of tegafur,uracil, and 5-fluorouracil after oral administration of a 1∶4 tegafur and uracil combination

The effects of gastrectomy on the pharmacokinetics of UFT, a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 14, were examined in 26 patients with macroscopic State I gastric cancer. In all, 200 mg UFT (in terms of tegafur) was given to 17 patients who underwent partial gastrectomy (9 cases of Billroth I reconstruction, 8 cases of Billroth II reconstruction) and to 9 patients who underwent total gastrectomy with modified Roux-en-Y reconstruction. Before the operation, the area under the curve (AUC) for tegafur, uracil, and 5-fluorouracil (5-FU) was 79.28±26.88, 4.41±1.78, and 0.51±0.20 g h ml^–1, respectively. Partial (Billroth I and II) and total gastrectomy did not alter the AUC of tegafur, and partial gastrectomy using the Billroth I and II methods decreased the AUCs of uracil and 5-FU during the first 2 weeks postoperation. However, plasma levels of uracil and 5-FU reverted to preoperative values at 3 months postsurgery. Our findings show that when UFT is prescribed for patients treated in the early postoperative period following partial gastrectomy for cancer, dose increases and the timing of administration should be given close attention.     

Identification and kinetics of a β-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan

Irinotecan (7-ethyl-10-{4-[1-piperidino]-1-piperidino}carbonyloxycamptothecin), also known as CPT-11, is a promising semi-synthetic derivative of camptothecin with significant activity against a range of tumour types. The pharmacokinetic behaviour of its principal and presumedly active metabolite, SN-38 (7-ethyl-10-hydroxycamptothecin), displays wide inter-patient variation. During the high-performance liquid chromatographic (HPLC) analysis of plasma samples collected from a patient given CPT-11, we observed several unidentified peaks that were not present in pre-infusion samples. In this paper we describe the manner in which one of these was determined to be a -glucuronide of SN-38. The total plasma concentrations of this metabolite were quantified following digestion with -glucoronidase and were found to be greater than those of SN-38 in the patient studied. The elimination phases of the plasma concentration profile of SN-38 and its glucoronide were parallel, suggesting that the transformation of SN-38 to the glucuronide is the rate-limiting step in the elimination of SN-38 and could play a key role in its pharmacokinetics.This work was presented in part at the 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, 15–18 March 1994. L. P. Rivory is the recipient of an NHMRC/INSERM Exchange Fellowship     

Investigations on the pharmacokinetics of trofosfamide and its metabolites—first report of 4-hydroxy-trofosfamide kinetics in humans

Trofosfamide (TRO), like cyclophosphamide (CYCLO) and ifosfamide (IFO), is a prodrug oxazaphosphorine derivative that requires hepatic biotransformation to form the cytotoxically active 4-hydroxy derivative (4-hydroxy-TRO). Individual 4-hydroxyoxazaphosphorines and 4-hydroxy-TRO itself have not been demonstrated in humans up to now. For investigation of the principal pharmacokinetics of TRO and its metabolites, six tumour patients (49–65 years of age, Karnofsky index >70%) with normal liver and renal function were given a single oral dose of 600 mg/m² TRO. Plasma was sampled using a bedside technique. Individual 4-hydroxyoxazaphosphorines and TRO together with further metabolites were determined by a specially developed HPLC-UV method and a HPLC-MS method, respectively. With a short apparent half-life (1.2 h) and high apparent clearance (Cl/F 4.0 l/min), TRO was very quickly eliminated from plasma and highly converted to its metabolites, mainly 4-hydroxy-TRO and IFO. In relation to the AUC values of TRO (1.0) the following molar quotients were calculated: 1.59 (4-hydroxy-TRO), 0.40 (4-hydroxy-IFO), 6.90 (IFO) and 0.74 (CYCLO). C_max values were in the range 10–13 mol/l for TRO, 4-hydroxy-TRO and IFO and in the range 1.5–4.0 mol/l for CYCLO, 2- and 3-dechloroethyl-IFO and 4-hydroxy-IFO. Kinetic data indicate that 4-hydroxy-IFO is formed by both hydroxylation of TRO and exocyclic N-dechloroethylation of 4-hydroxy-TRO. 4-hydroxy-CYCLO was not detected above the quantification limit of the method. Only mild haemodepressive side effects were observed after oral administration of 600 mg/m² TRO. In relation to known data for IFO, TRO is much more 4-hydroxylated than IFO. The high 4-hydroxy-TRO/TRO ratio found suggests that TRO is a promising tumourstatic agent.     

9-β-D-Arabinofuranosyl-2-fluoroadenine 5′-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma

Summary The pharmacokinetics of 9--D-arabinofuranosyl-2-fluoroadenine (F-ara-A) in plasma and its biologically active 5-triphosphate (F-ara-ATP) in leukemic cells obtained from the peripheral blood and bone marrow was evaluated in patients with hematologic malignancies subsequent to the first dose of 20–125 mg/m² per day for 5 days of F-ara-A 5-monophosphate (F-ara-AMP) administered as an IV bolus over 30 min. The terminal half-lives of elimination of both F-ara-A (8 h) in plasma and intracellular F-ara-ATP (15 h) were not dependent upon the dose of F-ara-AMP. The area under the concentration x time curves for F-ara-A and F-ara-ATP, on the other hand, were increased in proportion to the prodrug dose. There was a high correlation between F-ara-ATP levels in circulating leukemic cells and those in bone marrow cells aspirated at the same time. DNA-synthetic capacity of leukemic cells was inversely related to the associated F-ara-ATP concentration. A linear trend was noted when F-ara-ATP levels in pretreatment peripheral blood leukemic cells incubated with F-ara-A in vitro were compared with the amount of F-ara-A that was incorporated into nucleic acids. Finally, F-ara-ATP concentrations were three times higher in bone marrow cells from patients with lymphomatous bone marrow involvement than from those without evidence of marrow disease.Supported in part by grants CA28153 and CA32839 from the National Cancer Institute, United States Department of Health and Human Services     

Negative Impact of Chemotherapy on Breast Cancer Patients QOL - Utility of Antiemetic Treatment Guidelines and the Role of Race

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is one of the most important worries ofcancer patients. Although not life-threatening, it has a great negative impact on quality of life (QOL). Objective:The aim of this study was to determine the impact of CINV (i.e., acute and delayed) on breast cancer patientsQOL and to discern opinions related with antiemetic guidelines used dependent on the three main races inMalaysia (Malay, Chinese, Indian). Methods: In this longitudinal prospective observational study, 158 breastcancer patients treated with chemotherapy were interviewed and valid questionnaires (MANE and ONEM) wereused to report the impact of CINV on their QOL within the first 24 hours and after 3 to 5 days of chemotherapytreatment. Results: The main result was that delayed CINV has an impact on QOL greater than acute CINV. Theimpact of nausea was reportedly higher than that of vomiting. Also differences in race i.e., genetic polymorphisms(pharmacogenomics) influenced the utility of antiemetic treatments and patients opinions. Conclusion: Based onthe results of our study a new guideline for antiemetic treatment should be used to reduce the impact of CINVon QOL, taking into account variation in genetic polymorphisms among the three races in Malaysia.     

Addressing the Future Burden of Cancer and Its Impact on the Oncology Workforce: Where Is Cancer Prevention and Control?

The need for cancer professionals has never been more urgent than it is today. Reports project serious shortages by 2020 of oncology health care providers. Although many plans have been proposed, no role for prevention has been described. In response, a 2-day symposium was held in 2009 at The University of Texas MD Anderson Cancer Center to capture the current status of the cancer prevention workforce and begin to identify gaps in the workforce. Five working groups were organized around the following topic areas: (a) health policy and advocacy; (b) translation to the community; (c) integrating cancer prevention into clinical practice; (d) health services infrastructure and economics; and (e) discovery, research, and technology. Along with specific recommendations on these topics, the working groups identified two additional major themes: the difficulty of defining areas within the field (including barriers to communication) and lack of sufficient funding. These interdependent issues synergistically impede progress in preventing cancer; they are explored in detail in this synthesis, and recommendations for actions to address them are presented. Progress in cancer prevention should be a major national and international goal. To achieve this goal, ensuring the health of the workforce in cancer prevention and control is imperative.     

Impact of ERβ and CD44 expression on the prognosis of patients with stage II colon cancer

The correlation of ER??/CD44 expression and progression of patients with stage II of colon cancer were explored in this work. A total of 220 paraffin-embedded specimens with stage II colon cancer from 1995 to 2003 were included for assessing ER?? and CD44 by immunohistochemistry in normal mucosa and tumor tissues. Kaplen?CMeier method, log?Crank test, and the Cox proportional hazards regression model were used to analyze the overall survival data. ROC curve was used to describe the capacity of variables in prognosis prediction. Jackknife method was used to perform cross validation of predictions. The survival rates were significantly different between the patients with high expression and low expression of CD44-tumor tissues (61?% vs. 90?%, p?<?0.0001) and between the patients with high expression and low expression of ER??-tumor tissue (99?% vs. 36?%, p?<?0.0001), respectively. In addition, the interaction between expression of ER?? and CD44 was found that the impact of CD44 to the overall survive appeared only when expression of ER?? was low; and the high expression of ER??-tumor could be regarded as a protective factor for overall survival. This study suggest that low expression of ER??-tumor and high expression of CD44-tumor are risk factors for overall survival in patients with stage II colon cancer.     

TikTok – Potential Impact on the Use of Smokeless Tobacco and Betel Quid by Young People

Introduction: TikTok has gained increasing popularity over the past year. The social media may affect awareness and perceptions of betel quid (BQ) and smokeless tobacco (SLT) by utilizing content generated by TikTok users. The purpose of this study is to examine how BQ and SLT are portrayed on TikTok. Methods: The 28 most viewed hashtag-based keywords were used to identify popular BQ and SLT-related videos on TikTok (n=513) from June 2018 to September 2021. Two researchers independently coded the number of likes, shares, views, user category and themes. Results: A final sample of 513 videos containing BQ and SLT that met the study criteria were included. Collectively, these videos were viewed over 725 million times, with a median ‘view’ count of 17,300 (range 152–155,000,000) and a median ‘likes’ count of 831 (range 4–2,400,000) and a median ‘share’ count of 21 (range 0–48,400). Majority of the videos showed BQ and SLT use positively i.e promoting the product (390/513; 76%) and these had more than 686 million times views. Neutral depictions of BQ and SLT use were viewed 15 million times (72/513; 14%) and negative portrayals of BQ and SLT have been viewed 193 million times (105/808; 13%). The video themes included ‘life style’ (349/513; 68.0%), ‘marketing’ (62/513; 12.09%), ‘comedy’ (44/513; 8.6%), ‘warning’ (25/513; 4.87%), ‘awareness’ (12/513; 2.3%), ‘sports and other’ (12/513; 2.3%) and social events or culture (9/513; 1.75%). Conclusion: Our results demonstrated that video clips related to BQ and SLT on TikTok, a fast-growing, popular video-sharing platform among teens, which is available with no age restrictions has been viewed multiple times. Majority (76%) promoted these two products, that could be detrimental to oral health. Therefore, the age restrictions especially for the videos containing BQ and SLT is mandatory in order to reduce the potential exposure of adolescents/young adults.     

Combination therapy in cancer：effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Validated preclinical studies have provided evidence that anti-vascular endothelial growth factor (VEGF) compounds enhance the activity of subsequent antitumor therapy, but the mechanism of this potentiation is far from clear. The most widespread explanation is enhanced delivery of therapeutics due to vascular remodeling, lower interstitial pres-sure, and increased blood lfow. While the antiangiogenic effects on vascular morphology have been fairly consistent in both preclinical and clinical settings, the improvement of tumor vessel function is debated. This review focuses on the effect of anti-VEGF therapy on tumor microenvironment morphology and functions, and its therapeutic beneifts when combined with other therapies. The uptake and spatial distribution of chemotherapeutic agents into the tumor after anti-VEGF are examined.     

Impact of a Hospital''''s Workload on Clinical Outcome after Resection for Carcinoma of the Esophagus

Surgery for esophageal cancer is a demanding procedure associated with a high rate (30%-40%) of post-operative complications.Therefore,for esophageal cancer surgery,not only must the surgeonbe trained for preoperative preparation,operative therapy,and post-operative management,but also theentire hospital setting including physicians of different specialties and intensive care units.In the past fewyears publications have been particularly concerned with comparing the outcomes of high-volume centersand other hospitals in cases of various tumor operations.Due to more experience,increased frequencyof cases and better training conditions in high-volume centers,esophagectomies have been shown to havebetter outcomes,especially hospital mortality,when performed there than in centers performing them withless frequency.This review of the current literature for esophageal cancer surgery shows a clear reductionof postoperative mortality with increasing case volume per year.Single papers have analysed the mainreasons for this phenomenon and showed that postoperative complication rates are lower in high-volume-hospitals and their management of complications is more succesful.In conclusion,the analysis shows thatonly with the experience of more than 20 esophagectomies per year a significant reduction of the mortalitydown to <5% can be achieved.     

Effects of lysophosphatidic acid and its receptors LPA⅓ on radiation pneumonitis

Radiation pneumonitis (RP) is a serious complication of radiation therapy for thoracic tumors. Lysophosphatidic acid (LPA) and its receptors LPA? were reported to participate in the processes of inflammation. We tested the hypothesis that LPA and its receptors LPA?, take part in the pathogenesis of RP. In our study, irradiation increased LPA levels in the lung and expression of LPA?. To further determine the role of LPA?, we performed pharmacological knockout of LPA? by a specific antagonist, VPC-12249. On day 60 post-irradiation, RP was significantly alleviated in a dose-dependent manner in mice treated with VPC-12249, as shown by H&E staining, malondialdehyde (MDA, an indicator of oxidative damage) assay in lung, and concentrations of proinflammatory and profibrotic cytokines in plasma, including IL-1β, TNF-α, and TGF-β1. Additionally, VPC-12249 administration decreased the phosphorylation of IκB-α (the initial event that activates the NF-κB signal way), and expression of TGF-β1, CTGF, and α-SMA mRNA. Our findings suggest that LPA and LPA? may play a pivotal role in RP, and LPA-LPA? may serve as novel therapeutic targets for the treatment of RP.     

The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the β-catenin signaling pathway

Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/β-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a β-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ?-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ?-catenin levels. Moreover, 5-ASA significantly reduced ?-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ?-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ?-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.     

Cancers of the lung,head and neck on the rise：perspectives on the genotoxicity of air pollution

Outdoor air pollution has been recently classified as a class I human carcinogen by the World Health Organization （WHO）. Cumulative evidence from across the globe shows that polluted air is associated with increased risk of lung, head and neck, and nasopharyngeal cancers--all of which affect the upper aerodigestive tract. Importantly, these cancers have been previously linked to smoking. In this article, we review epidemiologic and experimental evidence of the genotoxic and mutagenic effects of air pollution on DNA, purportedly a key mechanism for cancer development. The alarming increase in cancers of the upper aerodigestive tract in Asia suggests a need to focus government efforts and research on reducing air pollution, promoting clean energy, and investigating the carcinogenic effects of air pollution on humans.     

Impact of a Hospital’s Workload on Clinical Outcome afterResection for Carcinoma of the Esophagus

Introduction Surgery for esophageal cancer is a demanding proce-dure, normally requiring an abdomino-thoracic approachand therefore speci?c experience. A high percentage ofpatients with esophageal cancer have risk factors for dif-ferent organ systems[2, 5, 6] . For this reason preoperativefunctional assessment and preparation of the patient, theanesthetic procedure with one-sided ventilation, and thesurgical technique have particular impact on the post-operative course. Esophageal surgery…