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Tumors are not immunologically silent but evolve and respond to therapy in the context of a continuous, bi-directional interaction with the host immune system. In line with this notion, several clinically successful chemotherapeutics have been shown to mediate antineoplastic effects as they (re)activate an anticancer immune response that is generally executed by lymphoid cells. Myeloid cells play a central role in this process, not only because they critically regulate the activity of T and B lymphocytes, but also because they exert direct tumoricidal effects, at least in some settings. Here, we discuss the impact of various myeloid cell populations, including macrophages, dendritic cells and myeloid-derived suppressor cells, on the efficacy of anticancer chemotherapy.

【背景・目的】がん化学療法に伴う味覚変化に対して, 看護者が行っているセルフケア教育の内容を明らかにすることである.【対象と方法】全国の500病院で働く病棟の副婦長1000名であり, 郵送法による質問紙調査を施行した.回収は634名 (回収率63.0%) であり, 該当なし, 記入不備を除く568名について分析を行った.セルフケア教育内容は自由記述により回答を求め, 内容分析を行った.【結果】看護者の約59%が患者・家族を対象として, がん化学療法に伴う味覚変化に関するセルフケア教育を行っていた.セルフケア教育内容で一番多い項目は, 「味覚変化時の食事」, 次いで「症状・徴候の観察」, 「味覚回復のための含嗽液」であった.教育内容としては, 味覚変化の原因と出現時期, 観察, 食事, 含嗽, 味覚刺激方法など一連のセルフケア教育を行っていることが明らかになった.味覚を回復するための含嗽液として, イソジン, レモン水, 氷水が高頻度に指導されていた.【結論】セルフケア教育内容として, 味覚変化時の食事指導は定着しつつある.しかし, 薬剤投与中の金属味への対処方法の教育は行われておらず教育内容に含める必要があることが明らかになった.さらに味覚を回復するために実践されているレモン水については, その効果が曖昧のまま指導されており介入研究が必要であることが示唆された.

Mesna, an SH-containing uroprotector, attenuates the lethal effect and hematological toxicity of vepeside and taxol, but did not reduce specific activities of the studied cytostatics in mice with transplanted tumors. This selective antitoxic effect of mesna towards vepeside and taxol allows to intensify the anticancer chemotherapy with these highly effective but extremely toxic cytostatics and to improve the efficiency of anticancer therapy.

BACKGROUND: The deleterious effect of blood transfusions on survival has been reported in patients with cancers of various organs. However, it remains unclear whether there is any adverse effect of blood transfusion when the patients are administered anticancer drugs after surgery for gastric cancers.METHODS: Data from patients with gastric resection for advanced gastric cancer were retrospectively analyzed to determine the influence of perioperative blood transfusion on the survival rate. All patients were administered anticancer drugs (mitomycin C [MMC] and tegafur-uracil [UFT]). Sixty-nine (33%) of 208 patients received blood transfusion perioperatively, while 139 patients (67%) did not receive transfusion. Multivariate analysis of clinicopathologic prognostic factors, including blood transfusion, was performed. Lymphocyte subsets were measured to investigate the immunosuppressive effect of blood transfusion.RESULTS: The 5-year survival rate was 48.8% in the 69 transfused patients and 66.9% in the 139 non-transfused patients ( P0.01). Cox's multiple regression analysis showed that, when patients received anticancer drugs, perioperative blood transfusion was not a significant factor affecting survival after the gastric cancer surgery. However, the CD4/CD8 ratio at 3 months after the surgery was significantly lower in the transfused group than in the non-transfused group.CONCLUSION: Blood transfusion did not affect the survival of operated patients who received postoperative adjuvant chemotherapy. However, the finding that the ratio of CD4/CD8 after surgery was significantly higher in the non-transfused group than in the transfused group supports the notion that transfusion causes broad-spectrum immunosuppression.

Emesis is one of the most unpleasant and debilitating side effects of anticancer chemotherapy. In acute emesis (vomiting occurring 0-24 hours after chemotherapy administration), the 5-HT3 receptor antagonists and corticosteroids are highly effective, with few significant side effects, and can safely be combined. Delayed emesis (vomiting occurring >24 hours after chemotherapy administration), however, is both not well understood and less well controlled. Studies have yielded conflicting results concerning the use of 5-HT3 receptor antagonists alone in delayed emesis. The data of NK-1 receptor antagonists in the control of acute emesis, although promising, need confirmation in a properly designed study.

Many cancer-associated genes are alternatively spliced; their expression leads to the production of multiple splice variants. Although the functions of most of these variants are not well-defined, some have antagonistic activities related to regulated cell death mechanisms. In a number of cancers and cancer cell lines, the ratio of the splice variants is frequently shifted so that the anti-apoptotic splice variant predominates. This observation suggests that modification of splicing, which restores the proper ratio of alternatively spliced gene products, may reverse the malignant phenotype of the cells and offer a gene-specific form of anticancer chemotherapy. Our laboratory has extensively investigated the use of antisense oligonucleotides for shifting the splicing patterns of several genes. Potential application of this method for treatment of cancers, as well as of certain genetic disorders, is discussed.

We reviewed the infectious complications in 207 courses of anticancer chemotherapy to 93 patients with urogenital cancer. Thirty episodes (14.5%) of neutropenic fever containing 9 cases (4.3%) of infection were observed. Five patients (16.7%) had pyelonephritis, one (3.3%) had acute prostatitis, two (6.6%) had pneumonia and one (3.3%) had bacteraemia. Multivariate analysis revealed that the infectious complications during anticancer chemotherapy were mainly associated with urinary diversion, hydronephrosis and duration of severe neutropenia (

We present the unusual case of a 29-year-old man diagnosed in 1975 with papillary carcinoma of the thyroid metastatic to regional lymph nodes. The patient underwent surgical resection, postoperative iodine-131 (131I) radioablation and levothyroxine suppression. He was subsequently lost to follow-up. In 1991, he presented with extensive metastatic disease that was not demonstrable on whole-body 131I imaging, but was seen on computerized tomography and whole-body thallium chloride scanning. The patient was treated with cisplatin (Platinol) and doxorubicin (Adriamycin). Repeat 131I imaging after three cycles of chemotherapy showed significant 131I uptake in previously non-iodine-concentrating lesions. The patient was subsequently treated with 200 mCi 131I. We postulate this patient's non-iodine-concentrating thyroid cancer may have become functional by either a differentiating effect of chemotherapy on the tumor cells, or perhaps a selective cytotoxicity against nonfunctional, less differentiated papillary thyroid cancer cells, or both. This would allow more functional differentiated cells to overgrow and become the predominant cell type in the lesions. Chemotherapy may be beneficial in patients with advanced non-iodine-concentrating differentiated thyroid carcinoma by inducing radioiodine uptake and allowing subsequent radioiodine therapy. The possible mechanisms of induction of iodine uptake by chemotherapy are discussed.

Sarcoidosis or sarcoid reactions, which appear as FDG-avid lesions in oncologic patients, need to be differentiated from disseminated malignancies. We aimed to promote awareness of development of sarcoidosis or sarcoid reactions after antineoplastic therapy to avoid diagnostic errors with FDG-PET/CT findings and assess the utility of FDG-PET/CT for follow-up. We retrospectively reviewed radiological reports of FDG-PET/CT scans performed between January 2009 and December 2011. Among oncologic patients with more than 2 FDG-PET/CT scans, those with nearly symmetrical increases in FDG uptake in the hilar or mediastinal lymph nodes were identified, and those with known sarcoidosis, concurrent diagnoses of sarcoidosis with malignancy, or histopathologically proven malignancies were excluded. Then, only those cases were selected for which sarcoidosis or sarcoid reactions were diagnosed. Four of 376 oncologic cases met the criteria. At 9 months to 6 years after antineoplastic therapy, abnormal FDG uptakes were observed in the hilar, mediastinal, abdominal, pelvic, and inguinal nodes, and/or spleen and lung parenchyma with SUVmax up to 17.7. On the basis of these findings, 1 patient received anticancer chemotherapy because of tumor recurrence suspicion. A gradual decrease in FDG uptake was observed on subsequent PET/CT scans. Sarcoidosis or sarcoid reactions should be considered in differential diagnosis of oncologic patients who have developed FDG-avid lesions any time after antineoplastic therapy. FDG-PET/CT can be used for follow-up in nondiagnostic situations to detect decreases in FDG uptake due to presence of sarcoidal granulomas.

Aggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemotherapy, and new lead compounds are required for the development of drugs to treat this fatal disease. Recently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene (TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives. Among them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate. This result, as well as computational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these inhibitors.

Drug therapy for diseases of the central nervous system (CNS) involves the complicating factors of drug penetration across the blood-brain barrier (BBB), the therapeutic effect on the CNS, and the potential for adverse effects. This chapter looks at drug entry to the brain, anti-infectious drug therapy, anti-inflammatory therapy, anticancer chemotherapy of the nervous system, adverse CNS reactions caused by drugs.

Most cancers have multiple genetic alterations or abnormalities. It is seldom very useful by only using one anticancer drug. Human cancer is a refractory and resistant disease, and like HIV virus, it might need anticancer drug cocktail instead single drugs to dramatically control the progresses of the disease. Anticancer drug cocktail might be one of the good solutions for anticancer chemotherapy. How to combine use of anticancer drugs is a new problem and area of anticancer drug therapy. This editorial addresses this problem in depth.

A review of mishaps involving pediatric patients receiving anticancer chemotherapy was undertaken in order to assist intervention. Although the case literature is too sparse to provide definite recommendations, suggestions for management are made in the event of an error with a high risk (based on the case literature) of life-threatening toxicities. It is recommended that all incidents be reported in the literature in order to provide a basis for devising standard treatment protocols. It is also suggested that studies using animal models continue to be done in order to provide more experimental data about toxicities and potentially beneficial rescue therapies.

肺癌化学療法に伴う呼吸器感染症の発症要因を明らかにするため, 咽頭細菌叢構成菌と宿主感染防御能の経時的変動をprospectiveに解析した.対象は全身化学療法を施行した原発性肺癌患者20例で評価可能化学療法は32コースであった.呼吸器感染症発症コース (A群) は15コース, 非発症コース (B群) は17コースであった.A群では咽頭細菌叢構成菌は呼吸器病原菌を化学療法前後で持続的に, もしくは化学療法後, 新たに分離する変動パターンをとる傾向を認めた.両群間で化学療法前PS不良例, 白血球数nadirおよび咽頭細菌叢構成菌の変動パターンに有意な差異を認めた.多変量解析の結果から, 咽頭細菌叢構成菌の変動と化学療法前PSが呼吸器感染症発症に影響を及ぼす重要な要因であると考えられた.以上より, 肺癌化学療法に伴う呼吸器感染症の発症には咽頭細菌叢構成菌の変動と宿主感染防御能の低下の両者が密接に関連していることが示唆された.

Anticancer chemotherapy is strongly hampered by the low therapeutic index of most anticancer drugs and the development of chemoresistance. Therefore, there is a continued need for the identification of new molecular targets in order to selectively hit cancer cells. RNA has been recently validated as a cancer target by the use of different specific ligands and/or by different agents able to destroy its diverse forms. The ability of synthetic polyamines to interact and to alter the RNA structure has been already reported. In the present paper the interaction and the ability to damage RNA structure by several synthetic polyamines were evaluated and quantified by microfluid capillary electrophoresis. This technique allowed us to visualize both the RNA impairment through different electropherograms and to assess the RNA integrity number. Finally, the ability to discriminate between RNA and DNA by these synthetic polyamines was also evaluated.

Among the differentiation-related changes in neuroblastoma are expressions of mdr-1 and bcl-2, which may be potentially related to the resistance to anticancer chemotherapy. In the present study, the authors performed an immunohistochemical analysis of mdr-1 and bcl-2 expressions in 30 neuroblastomas using monoclonal anti-P-glycoprotein(mdr-1 product) antibody and monoclonal anti-bcl-2 antibody to investigate the significance of their expression. The overall incidence of mdr-1 and bcl-2 expressions were 53.3% (16/30) and 93.3% (28/30), respectively. The expressions of mdr-1 and bcl-2 didn't seem to be related to the status of preoperative chemotherapy or stage of disease. The expression of mdr-1 was closely related to the differentiation of tumor cells (p0.01), especially to the neuronal differentiation. The bcl-2 expression was so common that it seemed to be indigenous to this neoplasm. The overall findings suggested that the expression of mdr-1 is one of the differentiation markers, while bcl-2 expression may partly explain the reasons for the relatively poor prognosis of neuroblastoma by the resistance to anticancer chemotherapy, which is a major therapeutic tool for this peculiar neoplasm.

107 Background: Our hospital is a cancer-specific facility that treats patients from diagnosis to terminal care. We evaluate the possibility of effective cancer chemotherapies for patients referred to our palliative care unit from other hospitals through case conferences in our institution. Even the patients referred to the palliative care unit of our institution are sometimes assessed as “very likely to be improved by standard or semi-standard treatment” by the palliative care and oncologic teams in our institution. We surveyed inappropriate cases that were mistakenly assessed as indicated for terminal care in their previous hospital. Methods: We reviewed 1535 patients referred to our palliative care unit from other hospitals because of anticancer chemotherapy contraindications over a 3-year period. We determined the number of the patients who were thought to actually have indications for cancer chemotherapy. Results: During the case conferences, 31 (2.0%) of the 1535 patients were thought to have indications for cancer chemotherapies. Standard chemotherapies were administered in our hospital to 6 patients. Four of the 6 patients were alive at one year and recovered their social life. Conclusions: Prudent assessment using updated guidelines are needed at the time of patient referral of a hospice. Ethical problems clearly exist with patients who were mistakenly assessed as indicated for terminal care in their previous hospital. There remains room for discussion of whether it is an ethical problem to overturn the will of a patient having chosen best supportive care (including those for whom it was presented as the only option by previous doctors or those who made positively the choice themselves) and proceed with cancer treatment.

What you need to know Cancer is the leading cause of disease related death in teenagers and young adults (TYAs) in Western countries.1 2 In the UK, cancer in TYAs accounts for 9% and 15% of all male and female deaths respectively, and its incidence has risen by 19% since the mid-1990s, leading to 2300 new cases a year between 2011 and 2013.1 In Japan it accounted for nearly 7000 deaths between 2000 and 2006.3 TYA cancer survivors are likely to live for many decades but are at risk of late effects of their treatment. This article provides information for generalists on late effects of anticancer chemotherapy (see infographic and supplementary table A) that may affect quality of life. Radiotherapy related effects are not discussed but are summarised elsewhere.4 There is no internationally accepted age definition for TYAs. In the UK, TYA age is 15-24 years, whereas the US National Cancer Institute defines adolescents and young adults as aged 15-39 years. In this review we use the UK definition of 15-24 years. #### Sources and selection criteria This article is an evidence based review of late effects of chemotherapy in teenagers and young adults (TYAs). Our review encompasses studies using all age ranges termed as TYA or adolescents and young adult (AYA). We searched PubMed and the Cochrane databases between 1990 and 2016 using the search terms “teenage and young …

Over the past five years, a considerable number of new and promising compounds for anticancer chemotherapy has been identified and studied in early clinical trials. Most important, topoisomerase I inh

Background In relation to the regional project UFAONCOEMA, at the enterprise level, a set of goals were fixed. They concerned: efficacy, efficiency, quality and performance safety. Among the quality goals, monitoring of waiting time for antiblastic chemotherapies was chosen as an indicator. Purpose The purpose was to assess, for two UFA (antiblastic drugs unit) which joined the UFAONCOEMA project, whether waiting times met the requirements of a maximum of 60 min, set at the enterprise level, according to the standard requirements adopted by other reference enterprises. Material and methods Times were monitored over a period of 3 months. Monitoring started from therapy’s online confirmation by the prescriber, to pharmacist validation, to preparation and delivery by nurses, and ended when the unit received that therapy. Therapies for 2018 patients in the oncology and haematology day hospital (DH) were evaluated. It has been considered that after verifying the appropriateness of the prescription, validation starts at about 8.15am, and preparation in a clean room starts at about 8.45am, due to set up of the laminar flow hood and sterile field. Results From when it is possible to make the preparation to the moment of delivery to the unit, under optimal conditions (3 nurses present, no extraordinary maintenance for the hood and/or UFA machinery), for therapies confirmed the same morning when the administration is expected, waiting times are 60 min for oncology and 57 min for haematology. Considering that therapies for the afternoon shift in the oncology DH and therapies confirmed on time for the following day are made and sent before 1.30pm, waiting time for those patients (10% of therapies) is zero, so the average waiting time reduces to 56 min. Conclusion This assessment shows that the average waiting times are included in a range of fixed requirements. 32% of morning therapies reach the applicant units within 50 mins. Transportation time (10 min) to the oncology DH, even it does not negatively affect the achievement of the goal, can be reduced with future transfer of the UFA centre in that unit. An increase in confirmed steady therapies for the day after can further reduce waiting time. No conflict of interest.

Therapeutic success of anticancer chemotherapy needs appropriate dosing. Clearly, the efficacy of chemotherapy is strictly dose dependent. Unfortunately side effects are dose dependent as well. Thereby, dosing of chemotherapeutic drugs is a delicate balancing act between killing tumor cells and severe toxicity in other tissues. Unfortunately, this delicate balancing act is done in mere blind flight.

The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity.

Alkylating agents are frequently used in many established anticancer chemotherapies. They alkylate the genomic DNA at various sites. Alkylation of the guanine at the O6-position is cytotoxic, it has the strongest mutagenic potential, as well as can cause the tumor development. Alkyl groups at the O6-position of guanine are removed by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The effectiveness of alkylating chemotherapy is limited by MGMT in cancer cells and adverse toxic side effects in normal cells. Different approaches consisting in the modulation of the MGMT expression and activity are under development now to improve the cancer chemotherapy. They include two main directions, in particular, the increase in chemosensitivity of cancer cells to alkylating drugs and the protection of normal cells from the toxic side effects of chemotherapy. This review is focused on current attempts to improve the alkylating chemotherapy of malignant tumours worldwide and state of the issue in Ukraine. Keywords: cancer chemotherapy, strategies of chemotherapy improvement, alkylating agents, O6-methylguanine-DNA methyltransferase (MGMT), DNA repair. Aлкілувальні сполуки часто застосовують у хіміотерапії раку. Вони алкілують геномну ДНК по багатьох сайтах. Алкілування гуаніну в позиції О6 цитотоксичне, має найсильніший мутагенний потенціал, а також може спричиняти розвиток вторинних пухлин. Алкільні групи у позиції O6 гуаніну видаляються за допомогою репаративного ферменту O6-метилгуанін-ДНК метилтрансферази (MGMT). Ефективність хіміотерапії з використанням O6алкілувальних сполук обмежена експресією MGMT у ракових клітинах та шкідливим побічним токсичним впливом у нормальних клітинах. Наразі для покращення хіміотерапії раку розробляють різні підходи до модуляції експресії та активності MGMT. До них належать два головних напрямки, а саме – підвищення хіміочутливості ракових клітин до алкілувальних ліків і захист нормальних клітин від токсичної дії хіміотерапії. Огляд зосереджено на існуючих спробах покращити хіміотерапію злоякісних пухлин за допомогою алкілувальних сполук як у світі, так і в Україні. Ключові слова: хіміотерапія раку, стратегії покращення хіміотерапії, алкілувальні сполуки, O6-метилгуанін-ДНК метилтрансфераза (MGMT), репарація ДНК. Алкилирующие соединения часто применяют в химиотерапии рака. Они алкилируют геномную ДНК по многим сайтам. Алкилирование гуанина в позиции O6 цитотоксично, имеет сильнейший мутагенный потенциал и может приводить к развитию вторичных опухолей. Алкильные группы в позиции O6 гуанина удаляются с помощью репаративного фермента O6-метилгуанин-ДНК метилтрансферазы (MGMT). Эффективность химиотерапии с использованием O6-алкилирующих соединений ограничена экспрессией MGMT в опухолевых клетках и неблагоприятным побочным токсическим действием в нормальных клетках. В настоящее время для улучшения химиотерапии рака разрабатываются разные подходы к модуляции экспрессии и активности MGMT. К ним принадлежат два основных направления, а именно – увеличение химиочувствительности раковых клеток к алкилирующим лекарствам и защита нормальных клеток от побочного влияния химиотерапии. Обзор сосредоточен на существующих попытках улучшить химиотерапию злокачественных опухолей с помощью алкилирующих соединений как в мире, так и в Украине. Ключевые слова: химиотерапия рака, стратегии улучшения химиотерапии, алкилирующие соединения, O6-метилгуанин-ДНК метилтрансфераза (MGMT), репарация ДНК

As the control of acute chemotherapy-induced emesis has improved, delayed emesis (occurring 24 h or more after treatment) has become the most bothersome vomiting problem. Delayed vomiting occurs after treatment with many anticancer drugs, but has been most often studied following cisplatin or combinations of cyclophosphamide and anthracyclines. The mechanism of this phenomenon is unknown. Empirical trials of antiemetic agents effective in controlling acute emesis identified the combination of metoclopramide and dexamethasone as useful in lessening delayed emesis after displatin in a randomized, placebo-controlled study. The specific serotonin receptor (5-HT3) antagonist ondansetron yielded results equivalent to the prior placebo results in a phase II trial using identical methodology in similar patients given cisplatin. Following anthracycline and cyclophosphamide combination chemotherapy, the delayed vomiting prevention observed with dexamethasone alone exceeds that of ondansetron. These observations suggest that delayed emesis is primarily mediated by neurotransmitters other than serotonin. Since delayed emesis occurs more frequently in patients who experience nausea and vomiting on the day they receive chemotherapy, tested combination antiemetic regimens, employing a 5-HT3 antagonist (either granisetron, metoclopramide, ondansetron or tropisetron), dexamethasone, and a benzodiazepine (lorazepam and alprazolam) should be routinely employed. This approach provides the best protection for acute and delayed emesis. Further research, looking beyond the specific 5-HT3 antagonists, provides the best strategy to improve the control of delayed symptoms.

We have studied the simultaneous administration of rhG-CSF with doxorubicin, the latter given by continuous infusion either intra-arterially or intravenously, in a group of patients with various sarcomas. This has enabled us to substantially increase the dosage intensity of doxorubicin with a marked decrease in both hematologic and oral toxicity. While the data concerning anti-tumor activity is preliminary we believe that this combination has been responsible for a substantial increase in the effectiveness of doxorubicin in controlling the sarcomas. No adverse effect from combining doxorubicin given by infusion with rhG-CSF has been noted to date.

One of the key obstacles against the success in cancer chemotherapy is the toxic and side effects of the chemotherapeutic agents. The avoidance of these toxic and side effects will greatly improve the therapeutic effects of anticancer drugs while decrease the pains of the patients. Here we show that activated carbon nanoparticles (ACNP), one of the mesoporous nanoparticles, can decrease the genotoxicity and teratogenicity of mitomycin C (MMC). To study the effects of ACNP on genotoxicity and teratogenicity of MMC, methods of PCE micronucleus test, Chinese hamster lung cell chromosome aberration experiment and rat teratogenicity were employed to observe the differences in genotoxicity and teratogenicity between ACNP-adsorbed MMC (ACNP-MMC) and free MMC. Results demonstrated that free MMC 0.16-5.0 microg/kg significantly increased the positive rate of PCE micronucleus test, the chromosome aberration rate and rat teratogenecity, but ACNP-MMC did not increased these heredity and reproduction toxicological indexes in a dose range of 0.625-10.0 microg/kg. From these results, it can be concluded that ACNP-MMC have significant effects to decrease the genotoxicity and teratogenicity effects of MMC. These results will have a considerable impact on the strategy of anticancer chemotherapy.

The synthesis of 2′-deoxy and 2′,3′-dideoxy derivatives of 1-s-D-ribofuranosyl-1,3,4,7-tetrahydro-2H-1,3-diazepin-2-one (2) was undertaken in order to find new cytidine deaminase (CDA) inhibitors and potential adjuvants in anticancer chemotherapy. Replacement of ribose by a 2-deoxyribose moiety led to compound 9 that appeared slightly more potent than 2 (Ki = 2.5 × 10−8 M). Remarkably, the corresponding α-2′-deoxynucleoside 10 acted as a very potent inhibitor of human placenta CDA, with a Ki = 7.5 × 10−8 M. Attempt to synthesize the 2′,3′-dideoxy derivative of 2 led to N-[4,5-dihydroxy-1-(2-oxo-2,3,4,7-tetrahydro[1,3] diazepin-1-yl)-pentyl]-2,2,2-trifluoroacetamide (13), which is devoid of CDA inhibitory activity.

In hospitals, the major part of the drugs is administered by intravenous way and the majority of the reconstitution of injectable drugs are carried out right before the administration to the patient by the nursing staff. The risks and errors related to the preparation and the administration of the injectable drugs are numerous. The standardization then the centralization of the preparations and reconstitution by the hospital pharmacy make it possible to reduce these various risks and errors. In addition to the preparation of the mixtures of parenteral nutrition as well as doses of anticancer chemotherapy, many other treatments can be taken in charge, such as antibiotics, antiemetics and pain treatments. Consequent equipment is necessary but the realization of these treatments proves non-overdrawn insofar as a certain quantity of production is reached. The reconstitution of the intravenous treatments by a centralized intravenous admixture service guarantees the chemical stability and the microbiological quality of the ready-to-use injectable drugs and contributes to the quality and the total management of the care of the patient.

The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I.

Cellular multidrug resistance, a common side-effect of anticancer chemotherapy frequently leading to failure of the treatment, has been characterized as an acquired resistance to several antimitotic drugs simultaneously. Multidrug resistance could mainly be attributed to the overexpression of the P-170 glycoprotein, considered as a drug-efflux pump encoded by the mdr 1 gene. Overexpression of this protein can be induced either by an accidental amplification or activation or both of the mdr 1 gene. Recent investigations focused on these mechanisms, aiming at a better understanding of the appearance of multidrug resistance during a chemotherapy. P-glycoprotein mediated drug resistance, however, is only one, albeit quite an important detoxification pathway, and some observations revealed genetic interactions with other systems. On the basis of this new knowledge, the development of novel therapeutic strategies to circumvent this clinical side-effect of cancer treatment has already begun.

Oral administration of the taxanes docetaxel and paclitaxel is hampered by their affinity for drug transporters, especially ABCB1 (P-glycoprotein, Pgp); extensive first-pass metabolism by cytochrome P450 3A (CYP3A); and poor drug solubility. Preclinical studies in Pgp-deficient and wild-type mice demonstrated that modulation of either Pgp or CYP3A resulted in high systemic exposure to docetaxel or paclitaxel. This concept could successfully be translated to clinical trials.

The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is focused mainly on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years.

Resume L'allongement de la duree de vie des patients atteints de cancer s'accompagne d'une plus grande frequence des complications renales liees aux chimiotherapies et depuis quelques annees on voit apparaitre dans les centres de dialyse des cancereux gueris ou en remission durable. Avant d'envisager la toxicite renale des traitements cytotoxiques il est indispensable d'eliminer les nombreuses autres causes (pre-renales, obstructives, iatrogenes ou liees au cancer) de dysfonctionnement renal. La toxicite renale de certains medicaments est importante car frequente et limitant leur emploi. Il s'agit du cisplatine, du cyclophosphamide et de l'ifosfamide, de la streptozocine, des nitrosourees, du methotrexate, de la mitomycine C et de l'IL2 recombinante. Les dangers des associations d'anti tumoraux, de l'administration concomitante d'autres medicaments nephrotoxiques (antibiotiques, anti-inflammatoires non steroidiens) et de la deshydratation extracellulaire engendree par les troubles digestifs doivent etre bien connus. L'evaluation soigneuse de la fonction renale avant toute chimiotherapie, l'utilisation de mesures preventives ayant fait leur preuve et une surveillance biologique a court, moyen et long terme devrait permettre de diminuer la frequence des complications renales en conservant, voire en ameliorant l'efficacite therapeutique.

Polymorphisms of the ABCB1 (MDR1) and ABCG2 (BCRP) genes were reported to alter the expression and function of these drug transporters. Both proteins are present at the main pharmacokinetic barriers including the blood-brain barrier. Data from 291 children with acute lymphoblastic leukaemia were analysed in this retrospective study. ABCB1 3435TC, 2677GT/A, 1236CT and ABCG2 421CA, 34GA genotypes were determined. Encephalopathy episodes were more frequent among those with ABCB1 3435TT genotype than in the 3435CC/CT group (odds ratio (OR) 3.5; P=0.03). Patients with the ABCG2 421A allele tended to have more complications than wild type homozygotes (OR=2.0; P=0.25). The rate of the adverse effect was similar in those harbouring no or only one of the predisposing genotypes, that is, either ABCB1 3435TT or ABCG2 421AA/AC. However, significantly more children suffered encephalopathy in the group with both predisposing genotypes (OR=12.3; P=0.005). In conclusion, these variations exert synergistic effect in predisposing patients to toxic neurological complications of chemotherapy.

A standardized Ginkgo biloba extract, EGb 761, may have protective effect against cisplatin-induced ototoxicity in rats.Cisplatin-induced ototoxicity is a major dose-limiting side effect in anticancer chemotherapy. Cisplatin-induced ototoxicity has been correlated to depletion of the cochlear antioxidant system and increased lipid peroxidation. EGb 761 contains potent antioxidants capable of scavenging free radicals, inhibiting nitric oxide synthesis, reducing lipid peroxidation, and protecting against apoptosis. The purpose of this study was to investigate the effect of EGb 761 on cisplatin-induced ototoxicity in rats.Male Wistar rats were divided into four groups and were treated as follows: 1) vehicle control; 2) cisplatin (13 mg/kg, intraperitoneally) plus vehicle; 3) EGb 761 (200 mg/kg, intraperitoneally); and 4) EGb 761 plus cisplatin. Auditory brainstem responses (ABRs) were measured pretreatment and 72 hours posttreatment, and threshold shifts were analyzed. Endocochlear potentials (EPs) were also obtained at 72 hours posttreatment. Cochleae were harvested and processed for scanning electron microscopy after completion of auditory testing.Cisplatin-treated rats showed significant ABR threshold shifts across all frequencies (click, and 2-, 4-, 8-, 16-, and 32-kHz tones) compared with each of the other groups (p0.001). Rats treated with EGb 761 plus cisplatin did not show significant ABR threshold shifts (p0.05). Similarly, the EPs of cisplatin-treated rats were decreased significantly approximately 50% in comparison with the other groups (p0.001). The EPs of EGb 761 plus cisplatin-treated rats were decreased less than 20% compared with vehicle control group or the EGb 761 only group (p0.01). The scanning electron microscopy observation indicated severe outer hair cell loss in the basal turn of cochleae of cisplatin-treated rats, whereas outer hair cells remained intact in the rats treated with EGb 761 plus cisplatin.These results demonstrate that EGb 761 protects against cisplatin-induced ototoxicity.

Acquired and intrinsic multidrug resistance is the major reason for the failure of anticancer chemotherapy. The most important component of clinical multidrug resistance is mediated by P-glycoprotein (Pgp), an ABC transporter encoded by the MDR1 gene and expressed on the membrane of tumor and normal cells. Sensitive and reproducible detection of Pgp expression and function are critical for the development of new MDR1 drugs and clinical protocols aimed at modulating Pgp-mediated multidrug resistance. The most commonly used methods for detecting Pgp distribution and functional activity have major flaws when used in routine clinical diagnostics. In this chapter, we describe and compare these techniques and introduce a new method for simultaneous detection of Pgp expression and function--the UIC2 Shift assay.

The aim of the study was to evaluate whether IFN-alpha/beta-inducible MxA protein expression in children receiving anticancer treatment can be used as an indicator for virus infections during the febrile episodes. Twenty-six children with mainly hematological malignancies entered the study. Children with laboratory-confirmed virus infections had clearly elevated MxA protein levels compared to their counterparts with bacterial or unknown etiology. MxA protein expression increased moderately following the administration of cytostatic agents, even though these children had no clinical signs of infection.

Tubercular lesion may coexist with malignancy in various sites resulting in dfficulties in diagnosing the conditions. A case of carcinoma caecum associated with tubercular lesion in the same site is reported. The patient have completed the antitubercular therapy and is now on regular anticancer chemotherapy. Till now the patient is doing fine. (Med J Indones 2005; 11: 128-30) Keywords : Carcinoma Caecum, Intestinal Tuberculosis, Management

Several pteridine analogues 4-13, 23-26 have been synthesized and tested in vitro against three cancer cell lines, MCF7 (breast), NCI-H460 (lung) and SF-268 (CNS). All tested pteridines can serve as novel templates for the anticancer chemotherapy and can serve as new leads in cancer chemotherapy.

Between April 10 and June 9, 2000, 91 owners of cats and dogs that were being or had been treated with anticancer chemotherapy were given a questionnaire designed to obtain information about their experiences as a result of the discovery and treatment of the disease, the efficacy and side effects of the treatment and their perceptions of the procedures associated with the administration of the drugs. Nearly all of the owners felt that the treatment was worthwhile. The level of observed side effects was low. Well over half of the owners believed that their animal had lived longer than it would have if it had not been treated and that its general wellbeing had improved. In general, they felt that the treatment had been rewarding and that any adverse side effects had been outweighed by the positive experiences during the treatment; they felt that they had been well informed and that their animals had benefited from the treatment.

The enantioselectivity of enzymes, namely the property of enzymes to recognise and metabolise only one of the two enantiomers of chiral molecules, is related to the chiral structure of the enzymes, reflecting the three-dimensional folding of the polypeptide backbone and the orientation of the amino acid side chains in the folded molecule. Because of the chirality of the amino acids (L), the chemistry of life should be highly sensitive to different enantiomers of chiral substrates. However, in a world consisting only of D-nucleosides and L-amino acids, an enzyme which lacks enantio-selectivity does not reduce its fitness, since there is no chance of molecular misunderstanding when no other choice is available. Thus, although enantioselectivity is theoretically essential for life we do not expect to be always present among the biochemical properties of enzymes. If this is the case for key enzymes involved in virus infection or cancer, how to exploit such lack of enantioselectivity for a novel approach to antiviral or anticancer chemotherapy? The present review will discuss the possible lack of enantioselectivity of enzymes and its relevance for the developing of novel drugs with the inverted optical configuration.

We describe the case of a patient with a prior history of acute intermittent porphyria (AIP) who needed the administration of anticancer drugs. Our experience with this patient and the limited experience reported in the literature show that it is probably safe to administer some chemotherapeutic agents, but it is important to prevent (or to minimize) the toxicities of these chemotherapeutic agents, as they seem to put the patient at major risk of an AIP crisis. Hematin and supportive treatments were useful treatments in our patient.