Types Of Chemotherapeutic Agents Research Articles

CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFβ, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

Multidisciplinary Taiwan consensus for the use of conventional TACE in hepatocellular carcinoma treatment.

Developed in early 1980s, transarterial chemoembolization (TACE) with Lipiodol was adopted globally after large-scale randomized control trials and meta-analyses proving its effectiveness were completed. Also known as "conventional TACE" (cTACE), TACE is currently the first-line treatment for patients with unresectable intermediate stage hepatocellular carcinoma (HCC) and delivers both ischemic and cytotoxic effects to targeted tumors. Although new technology and clinical studies have contributed to a more comprehensive understanding of when and how to apply this widely-adopted therapeutic modality, some of these new findings and techniques have yet to be incorporated into a guideline appropriate for Taiwan. In addition, differences in the underlying liver pathologies and treatment practices for transcatheter embolization between Taiwan and other Asian or Western populations have not been adequately addressed, with significant variations in the cTACE protocols adopted in different parts of the world. These mainly revolve around the amount and type of chemotherapeutic agents used, the type of embolic materials, reliance on Lipiodol, and the degree of selectiveness in catheter positioning. Subsequently, interpreting and comparing results obtained from different centers in a systematic fashion remain difficult, even for experienced practitioners. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to devise modernized recommendations that reflect recent clinical experiences, as well as cTACE protocols which are tailored for use in Taiwan. The conclusions of this expert panel are described herein.

The role of the PTEN/mTOR axis in clinical response of rectal cancer patients.

Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance. Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan-Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed. Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade. The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

To Study Herbal Monograph of Zingiber Officinale

Ginger (Zingiber officinale.) Belongs to the Zingiberaceae family. The health-promoting idea of ginger is said to be rich in its phytochemistry. This study aims to review current evidence on the effects of ginger as an anti-inflammatory and anti-oxidative. Gastrointestinal cancer (GI), a cancer of the various organs in the digestive system, is one of the most common cancers in the world. The mortality rate for some of these cancers is very high. Although many types of chemotherapeutic agents have been introduced in the last few decades to fight GI cancer, most of them are very expensive and have side effects. Therefore, compounds found in natural sources, which are considered safe and less expensive, are needed. Ginger (Zingiber officinale) is one of the most widely used natural products used as a spice and medicine to treat nausea, diarrhea, heartburn, heartburn, diarrhea, anorexia, infections, coughs and bronchitis. Experimental studies have shown that ginger and its active ingredients including 6-gingerol and 6-shogaol perform anti-cancer functions against GI cancer.

Treatment Intensity, not Age, Affects Survival Time of Patients with Advanced Pancreatic Cancer.

Despite older-aged individuals accounting for most patients with pancreatic cancer, elderly patients are still underrepresented in the clinical trials. Our study aims to identify treatment differences as well as to analyze survival times in the younger and older patient group. We evaluated the data of 97 pancreatic cancer patients (72 <75 years; 25 ≥75 years) receiving palliative chemotherapy. Age, comorbidity, body mass index (BMI), tumor localization, metastases, carbohydrate-antigen 19-9 (CA19-9) value, number and type of chemotherapeutic agents and treatment regimens used, treatment lines, toxicity and survival time were assessed. The age groups did not differ in their initial conditions (comorbidity, BMI, tumor characteristics). However, treatment intensity of patients ≥ 75 years was lower. Elderly patients received significantly fewer different chemotherapeutic agents and therapeutic regimens, therapy lines and fewer combination chemotherapies. Moreover, elderly patients survived significantly shorter (7.6 vs. 12.7 months, p=0.001). In multivariance analysis, a significant negative influence on survival time was revealed for low therapy intensity (≤2 chemotherapeutics, ≤2 therapy lines), but not for age. In addition, therapy discontinuation and underweight were significantly associated with survival time. Not age per se but lower therapy intensity leads to a shorter overall survival in the elderly patient group.

Malus Domestica Peel Extract Counters Carboplatin Induced Fall in Red Blood Cell Count and Bone Marrow Erythroid Cell Percentage in Mice

Introduction: The Chemotherapy-Induced Anemia (CIA) is a complex phenomenon impacted by many treatments and patient related variables. Some variations within CIA are type of chemotherapeutic agent, dose and schedule of administration of agent, type as well as stage of cancer, time of intervention, age, gender, nutritional status and renal function. The variety of patient presentation and symptomatology in CIA is very thought-provoking while setting up widespread measures to oversee ideal administration of treatments. This study will be focused on protective role of apple peel extract (APPE) on carboplatin induced fall in blood RBC count bone marrow erythroid cell percentage in mice.Aims &amp; Objective: To evaluate the protective effect of Malus domestica peel extract on carboplatin induced fall in red blood cell count and bone marrow erythroid cell percentage in mice.Place and duration of study: The study was conducted at Pharmacology Department of Postgraduate Medical institute, Lahore in June 2016. The total duration of study was 1 month.Material &amp; Methods: Forty adult male mice were randomly divided into 5 groups (n=8) and maintained on standard diet and water adlibitum. Group A was negative control. Group B was disease control wherein each animal received one dose of 125mg/kg carboplatin intraperitoneally. Group C, D &amp; E experimental groups were administered same dose carboplatin followed by the ethanolic apple peel extract in three different single oral doses of 25, 50 &amp; 75mg/kg respectively for 7 days. Blood &amp; tissue sampling was done on the 8th day. Data was analyzed using Graf Pad prism 7.Results: Acute Carboplatin anaemia resulted in 4.01±0.851012/L RBC Count &amp; 21.6±1.06% bone marrow erythroid cell percentage in Disease Control Group B. Subsequent Apple peel extract administration in a dose of 25, 50 and 75mg/kg\ countered carboplatin induced fall in Groups C, D &amp; E, simultaneously raising RBC counts &amp; bone marrow erythroid cell percentage to (6.19±0.70×1012/L &amp; 21.3±1.28%) (6.56±0.37×1012/L &amp; 25.3±1.04%) and (6.26±0.74×1012/L &amp; 23.5±1.41%.) respectively. The increase in RBC as well as erythroid cell counts was most significant with the dose of 50mg/kg and nearing that of healthy control levels (Group A)Conclusion: Apple Peel Extract effectively prevented carboplatin induced fall in RBC count and erythroid cellpercentage and produced most significant results in a dose of 50 mg/kg.

Effect of Conventional Chemotherapy in Patients With Neuroendocrine Tumours: A Systematic Review

Background: Neuroendocrine tumours (NETs) are a wide-ranging group of neoplasms originating from neuroendocrine cells. In 2014 NETs incidence was 7 per 100000 people annually. The purpose of this systematic review is to evaluate the safety and efficacy of various types of chemotherapeutic agents on gastroenteropancreatic NETs (GEP NETs) and to determine which type of chemotherapy is the most effective for different tumour types, with minimum adverse events. To our knowledge, this study is the first systematic review that compares several types of chemotherapy and evaluates their safety and efficacy on GEP NETs. Methods: The study followed recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on reporting systematic reviews. The literature search for this systematic review was conducted using the following databases and search engines: Cochrane library, EMBASE, Google Scholar, PubMed, and Web of Science, from 1963 to 2020. Results: The review comprised 26 observational studies, and 5 randomized controlled trials (RCTs). The total number of subjects included in this study was 1783. Our study showed that the most effective treatment for Grade 3 NETs and Grade 3 neuroendocrine carcinomas was cisplatin/etoposide. Furthermore, capecitabin/temozolomide therapy has been shown to be most effective in Grade 1 and Grade 2 NETs. Conclusion: Therapy with two chemotherapeutic agents has been shown to be more effective than monotherapy and therapy with three chemotherapeutic agents. Unfortunately, our study has limitations and we urgently need RCTs or larger observational studies that will contain all the necessary efficacy and safety tools, and thus provide answers to our clinical questions.

Evaluation of Risk Factors Causing Ototoxicity in Childhood Cancers Located in the Head and Neck Region Treated With Platinum-based Chemotherapy.

The aim of this study is to evaluate risk factors contributing to the development of ototoxicity in children who received platinum-based chemotherapy for malignancies located in the head and neck region. Eighty-four children who received platinum-based chemotherapy were included. Audiologic evaluations were performed before and after each chemotherapy session through pure tone audiometry, distortion product otoacoustic emissions, and auditory brainstem response tests. Ototoxicity was evaluated using Brock, Muenster, and Chang classifications. Factors such as cranial irradiation, cumulative doses of cisplatin, age, sex, cotreatment with aminoglycosides, schedule of platinum, and type of chemotherapeutic agent were analyzed. Using χ2 tests, all risk factors were matched with the 3 ototoxicity classifications, and multivariate analyses were conducted using statistically significant risk factors. In univariate analyses, being between 5 and 12 years of age, cranial irradiation and being treated with both cisplatin and carboplatin were found to be related to ototoxicity in all 3 classifications. Logistic regression modeling analyses with these 3 risk factors showed that being between 5 and 12 years of age and being treated with both cisplatin and carboplatin significantly increased the risk of ototoxicity.

GOLD NANOPARTICLES AND CHEMOTHERAPEUTIC AGENTS

Gold nanoparticles (AuNPs) receive a great deal of attention for biomedical applications due to their unique properties to monitor intracellular delivery of therapeutic agents. Evidently, drug delivery is a compelling field of research due to the need of releasing medicine at specific locations in a controlled manner with a minimum amount of side effects. The present review focuses on the combination of AuNPs with different types of chemotherapeutic agents as potential drug delivery vehicles that can be used in cancer therapy

Abstract 1857: Proscillaridin A induces apoptosis and suppresses non-small cell lung cancer tumor growth via calcium-induced DR4 up-regulation

Abstract Non-small cell lung cancer (NSCLC) is the predominant histological type of lung cancer and is characterized by the highest mortality and incidence rates among these types of malignancies. Cardiac glycosides, a class of natural products, have been identified as a potential type of chemotherapeutic agent. This study aims to investigate the anti-cancer effects and the mechanisms of action of Proscillaridin A (P.A) in NSCLC cells. In vitro sodium-potassium pump (Na+/K+ ATPase) enzyme assays indicated that P.A is a direct Na+/K+ ATPase inhibitor. P.A showed potent cytotoxic effects in NSCLC cells at nanomolar levels. Treatment mechanism studies indicated that P.A elevated Ca2+ levels, activated the AMPK pathway and down-regulated phosphorylation of ACC and mTOR. Subsequently, P.A increased death receptor 4 (DR4) expression and down-regulated NF-κB. Interestingly, P.A selectively suppressed EGFR activation in EGFR mutant cells but not in EGFR wild-type cells. In vivo, P.A significantly suppressed tumor growth in nude mice compared to vehicle-treated mice. Compared with the Afatinib treatment group, P.A displayed less pharmaceutical toxicity, as the body weight of mice treated with P.A did not decrease as much as those treated with Afatinib. Consistent changes in protein levels were obtained from Western blotting analysis of tumors and cell lines. Immunohistochemistry analysis of the tumors from P.A-treated mice showed a significant suppression of EGFR phosphorylation (Tyr 1173) and reduction of the cell proliferation marker Ki67. Taken together, our results suggest that P.A is a promising anti-cancer therapeutic candidate for NSCLC. Acknowledgements This work was supported by the Macau Science Technology Development Fund (project code: 021/2013/A1, 005/2014/AMJ &amp; 010/2016/A1). Note: This abstract was not presented at the meeting. Citation Format: Run-Ze Li, Xing Xing Fan, Xiao- Jun Yao, Elaine L. Leung, Liang Liu. Proscillaridin A induces apoptosis and suppresses non-small cell lung cancer tumor growth via calcium-induced DR4 up-regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1857.

Abstract 2717: Role of NAD+ level by NQO1 enzymatic action in regulation of hair regrowth that prevents chemotherapy-induced alopecia

Abstract Various types of chemotherapeutic agents are widely used to treat a variety of human neoplasms. Nonetheless, its clinical use is hampered because of severe adverse side effects such as alopecia, neutropenia, pain, cachexia, conception impairment etc. Chemotherapy-induced alopecia (CIA) is one of the fundamental unsolved problems of clinical oncology that often encountered in cancer treatment. CIA has been reported to be caused by skin inflammation through oxidative stress, DNA damage, and inflammatory responses. However, the best remedy for CIA is still not established. In a new strategy, we show that WK0202 compound as a strong NQO1 substrate that modulates the intracellular NAD+ levels by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action and plays important role in hair regrowth response to single (cyclophosphamide-CYP) or combined (taxol, adriamycin and cyclophosphamide-TAC) cancer therapy. Particularly, we demonstrated that cellular NAD+ levels as well as SIRT1 activity and its expression was decreased in skin with hair follicles after CYP and TAC treatment, and PARP-1 hyperactivation was associated with CIA through increased nuclear factor (NF)-κB p65 and p53 acetylation in wild type, NQO1-/- and K14-/- C57BL/6 mice. However, an increase in NAD+ levels by WK0202 completely restored SIRT1 activity and its expression, and subsequently deacetylated NF-κB p65 and p53 in wild type, however not in NQO1-/- and K14-/- mice thereby attenuating CIA. Therefore, modulation of NAD+ levels by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated hair loss, including CIA. Citation Format: Dipendra Khadka, Gi-Su Oh, Hyung-Jin Kim, SeungHoon Lee, Su-bin Lee, Subham Sharma, Seon Young Kim, Tae Hwan Kwak, Sei-Hoon Yang, Hyuk Sim, Hong-Seob So. Role of NAD+ level by NQO1 enzymatic action in regulation of hair regrowth that prevents chemotherapy-induced alopecia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2717.

Establishment of imatinib-resistant gastrointestinal stromal tumor cell subline and investigation of its sensitivity to the chemomotherapeutic agents

Aim. To establish the subline of imatinib-resistant gastrointestinal stromal tumor (GISTs) cells and to evaluate its sensitivity to various types of chemotherapeutic agents. Methods. To establish imatinib-resistant subline, tumor cells of GIST T-1 line were cultured with gradually increasing doses of imatinib for 18 months. Sensitivity of GIST T-1 cells to imatinib was comparably evaluated every 3 months by using MTS-based colorimetric assay. Level of expression of proteins serving as apoptotic markers, was examined by Western blotting with appropriate monoclonal antibodies. After establishment of GIST T-1 cell line with the signs of resistance to target medication imatinib, its sensitivity to various groups of chemotherapy (doxorubicin, etoposide, vinblastine, paclitaxel and cys-platinum) was evaluated. Sensitivity of imatinib-resistant GIST T-1 cells to chemotherapy as well as the level of expression of proteins serving as apoptotic markers, was evaluated by using MTS-based colorimetric assay and Western blotting. Results. After 18 month of culturing GIST T1 cells in the presence of gradually increasing doses of imatinib, the sings of resistance to this drug were observed. The obtained subline of GIST T1 IM-108R cells was sensitive to all used chemotherapeutic agents. Doxorubicin, vinblastine and etoposide were found to be the most potent cytostatic agents against imatinib-resistant GIST T1 IM-108R cells. Conclusion. Imatinib-resistant GIST T1 subline cells are sensitive to various types of chemotherapeutic agents; the established GIST T1 IM-108R cell subline might be further used for screening for the most effective chemotherapeutic agents and novel synthesized compounds.

The Cytoprotective Effect of Crocin on Oxaliplatin Treated VERO cell line In Vitro Study

AbstractBackgroundCancer is a disease characterized by a shifted in the control mechanism that governs cell survival, proliferation and differentiation.There are many types of treatment to the cancer like surgery, radiation, chemotherapy, immunotherapy and others. Each of these above treatments has its indication effect and has Sid effect and / or adverse effect. The chemotherapy is one type of this treatment to the cancer that have the indication effect, side effect and adverse effect. There are many type of chemotherapeutic agent that used for this type of cancer one of them it is platinum compound (cisplatin, oxaliplatin and others).There are two types of limitation in the use of these agents one of them is the side effect which is neurotoxicity, Ototoxicity, nephrotoxicity, and etc. and the second one is the resistance of cancer cells to these agents.Aim of the studyTaste the cytoprotection effect of Crocin on oxaliplatin treated VERO cell lineMaterial and methods:-By using the tissue culture techniques which is a newly used techniques to check the cytotoxicity of many compound and the expected mechanism of action these techniques made a good jump in the research in many fieldIn this study we use VERO cell line and after exposure of this cell line firstly to different concentrations of oxaliplatin ( 1, 0.5, 0.25 and 0.125 mg/ml) for 48hr, secondly to different concentrations of Crocin (0.5, 0.25 and 0.125 mg/ ml ) for 48hr. And thirdly to mix concentrations of oxaliplatin and Crocin in 48hr for the VERO cell line and measure the cytotoxicity of these exposures by crystal violet test (C.V. test) to show and compare the effect of these agents specially the Crocin.The oxaliplatin has cytotoxic effect, its inhibitory concentration 50% (IC50) in 48hr is (0.031mg/ml) which is the maximum cytotoxic effect in vitro. While the Crocin don’t have cytotoxic effect at this tested concentration and for this cell line. After mixed different concentration of Crocin with different concentration of oxaliplatin the cytotoxicity of oxaliplatin reduce significantly.Conclusion:-From our study we can conclude the following:-The Crocin has cytoprotective effect. The Crocin has no anti tumor and anti proliferative activity within these tasted concentration and this cell line

Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy.

The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.

Antimicrobial efficacy of commercially available mouthrinses: An in vitro study

Introduction: Oral cavity ecosystem represents a dynamic pattern. An effective plaque control measure should target plaque formation before the mature plaque is formed. Various types of chemotherapeutic agents are coming up with different antimicrobial agents in them. Hence, this study has been undertaken to know whether these antimicrobial agents are effective on common microorganisms of oral cavity which directly and indirectly contributes to plaque formation Aim: The aim of this study was to determine antimicrobial efficacy of different mouthrinses against the oral pathogens in vitro. Materials and Methods: A total of seven mouthrinses were tested for their antimicrobial activity against three oral pathogens, namely, Streptococcus mutans (MTCC 890), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 10231) by well agar diffusion assay. Statistical analysis was performed using Kruskal–Wallis test. The level of significance used was P< 0.05. Results: Mouthrinse with chlorhexidine (CHX) gluconate, triclosan as main ingredients showed maximum zone of inhibition (P = 0.003) against streptococcal mutans and E. coli at 1:16 dilution and mouthrinse with CHX gluconate and zinc chloride showed maximum zone of inhibition at 1:16 dilution against Candida among seven mouthrinses used in the present study. It was also observed that zone of inhibition of all the mouthrinses decreased with the increase in dilution. Conclusion: Among mouthrinses formulations, CHX combined with other active ingredients was found to be more effective.

Chemotherapy-induced polyneuropathy: major agents and assessment by questionnaires.

Chemotherapy-induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. Therefore, the aim of this MiniReview was to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant differences between the neuropathic pain scales, which are most commonly used for assessing CIPN.

Secondary Leukemia After Chemotherapy and/or Radiotherapy for Gynecologic Neoplasia

Secondary leukemia is a known complication of chemotherapy and radiotherapy. It was generally recognized that leukemia secondary to chemotherapy was due to the use of alkylating agents in the treatment of ovarian cancer. Recently, many types of chemotherapeutic agents have been used in the treatment of gynecologic malignancies in addition to ovarian cancer. We analyzed the clinical characteristics and outcome of patients with recent onset of secondary leukemia after the treatment of gynecologic cancer to consider the diagnosis and management of secondary leukemia. We reviewed the clinical charts and follow-up data of patients with gynecologic malignancies treated in the past 20 years. During this period, 2482 newly diagnosed invasive gynecologic cancers were treated in our institution. All patients with secondary leukemia were analyzed for clinical background, latency period (interval between the diagnosis of primary carcinoma and the development of leukemia), treatment, and outcome. We also reviewed the literature for secondary leukemia under gynecology using the PubMed. Four patients were found to have developed secondary leukemia after the treatment of gynecologic malignancies during this period. The cumulative risk of secondary leukemia was approximately 0.38%. All patients received platinum-based chemotherapy. Two patients received combination chemotherapy and/or bone marrow transplantation, and 1 of these 2 patients lived more than 6 years but died of recurrent ovarian cancer. Long survival time might be expected in patients who show complete response to bone marrow transplantation and/or combination chemotherapy for secondary leukemia. In recent years, we have aggressively used various types of anticancer drugs for the treatment of not only ovarian cancer but also uterine cervical cancer and endometrial cancer. Physicians need to keep in mind the risk of secondary leukemia in the follow-up of long-term survivors after several courses of chemotherapy and radiotherapy.

Effects of xaliproden, a 5-HT1A agonist, on mechanical allodynia caused by chemotherapeutic agents in mice

In the present study we investigated whether xaliproden, a selective 5-HT1A receptor agonist, could relieve allodynia induced by three types of chemotherapeutic agents (paclitaxel, vincristine, and oxaliplatin) in mice. A single intraperitoneal injection of paclitaxel (5mg/kg), vincristine (0.1mg/kg), or oxaliplatin (3mg/kg) time-dependently increased punctate stimulation-evoked allodynia over 10–14 days; the intensities of allodynia were similar between the treatment groups. A single oral dose of xaliproden (0.3–3mg/kg) inhibited paclitaxel-induced allodynia in a dose-dependent manner. Xaliproden (3mg/kg) administration produced a slight and no suppression of vincristine-induced and oxaliplatin-induced allodynia, respectively. The firing response of the tibial nerve to punctate stimulation increased in mice that received paclitaxel or oxaliplatin. Xaliproden (3mg/kg) markedly inhibited the firing response in the mice treated with paclitaxel, while it partially inhibited the firing response in the oxaliplatin-treated animals. Vincristine did not significantly increase the tibial nerve response. Paclitaxel significantly increased the mRNA expression of 5-HT1A receptor in the dorsal root ganglia, but not in the spinal dorsal horn. In contrast, oxaliplatin significantly increased the mRNA expression of 5-HT1A receptor in the spinal dorsal horn, but not in the dorsal root ganglia. Vincristine did not affect the mRNA expression of 5-HT1A receptor in both these regions. These results suggest that xaliproden produces acute inhibition of mechanical allodynia induced by paclitaxel, but not by vincristine and oxaliplatin, via inhibition of the hyper-response of the primary afferent neurons.

Retrospective Analysis of Third-Line and Fourth-Line Chemotherapy for Advanced Non–Small-Cell Lung Cancer

Background The efficacy of third-line and further-line chemotherapy for advanced non–small-cell lung cancer (NSCLC) remains unknown. Patients and Methods We evaluated the clinical outcome of third- and fourth-line chemotherapy for the treatment of advanced NSCLC in consecutive patients who received first-line chemotherapy at our institute between July 2002 and June 2006. From a hospital-based registry, the following data were extracted: (a) patient characteristics, (b) type of chemotherapeutic agents, and (c) objective response and survival data. Results A total of 599 patients were included in this analysis. Overall, 69.3%, 38.4%, 17.7%, and 6.0% of the patients received second-, third-, fourth-, and fifth-line chemotherapy, respectively. Significant differences in age ( P < .0001), performance status at the start of first-line chemotherapy ( P < .0001), and histology ( P = .0175) were observed between patients who received third-line chemotherapy and those who did not. Docetaxel, gefitinib, and S-1 were the most frequently used regimens for third- or fourth-line chemotherapy. Five percent of the patients had participated in phase I trials of investigational new drugs. The objective response rates and disease control rates of third- and fourth-line chemotherapy were 17.0% and 34.4% and 11.3% and 24.5%, respectively. The median survival times (95% confidence interval [CI]) from the start of first-, second-, third-, and fourth-line chemotherapy until death were 15.3 months (95% CI, 13.8-16.5 months), 12.8 months (95% CI, 10.7-14.5 months), 12.0 months (95% CI, 9.3-14.2 months), and 9.9 months (95% CI, 8.6-12.0 months), respectively. Conclusion As many as 38% of patients with advanced NSCLC who received first-line chemotherapy could receive third-line chemotherapy. This result emphasizes the need for randomized controlled trials of third-line treatment in patients with advanced NSCLC.

Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy.

We report a novel approach for nanoparticle-based combination chemotherapy by concurrently incorporating two different types of drugs into a single polymeric nanoparticle with ratiometric control over the loading of the two drugs. By adapting metal alkoxide chemistry, we synthesize highly hydrophobic drug-poly-L-lactide (drug-PLA) conjugates, of which the polymer has the same chain length while the drug may differ. These drug-polymer conjugates are then encapsulated into lipid-coated polymeric nanoparticles through a single-step nanoprecipitation method. Using doxorubicin (DOX) and camptothecin (CPT) as two model chemotherapy drugs, various ratios of DOX-PLA and CPT-PLA conjugates are loaded into the nanoparticles with over 90% loading efficiency. The resulting nanoparticles are uniform in size, size distribution and surface charge. The loading yield of DOX and CPT in the particles can be precisely controlled by simply adjusting the DOX-PLA:CPT-PLA molar ratio. Cellular cytotoxicity results show that the dual-drug loaded nanoparticles are superior to the corresponding cocktail mixtures of single-drug loaded nanoparticles. This dual-drug delivery approach offers a solution to the long-standing challenge in ratiometric control over the loading of different types of drugs onto the same drug delivery vehicle. We expect that this approach can be exploited for many types of chemotherapeutic agents containing hydroxyl groups and thus enable codelivery of various drug combinations for combinatorial treatments of diseases.