Progress in cancer research and multidisciplinary therapy has led to improvements in prognosis for cancer patients. Bone health has been regarded as important in terms of long-term quality of life. Lately, cancer treatment-induced bone loss (CTIBL) associated with endocrine therapy, chemotherapy, and radiotherapy has attracted considerable attention. In this article we introduce the latest results of clinical trials around the world on CTIBL associated with breast cancer treatment, in particular aromatase inhibitor associated bone loss (AIBL) . We also explain the efficacy of using bisphosphonate or Denosumab with endocrine therapy, the latest management strategy for bone health.

Breast cancer most frequently causes bone metastases in solid tumors. It has been known that there is a vicious cycle consisting of tumor cells, osteoblasts, osteoclasts and various humoral factors in osteolytic lesions. Although systemic therapy is a main treatment of bone metastases, local therapies, such as radiotherapy and surgical therapy, are also promptly needed when bone-related complications occur. In recent years, anti-osteoclast agents, bisphosphonates significantly contribute to the delay of occurrence of bone-related complications. Postoperative adjuvant therapy significantly reduces the incidence of recurrence in breast cancer patients. Chemotherapy and LH-RH agonists cause ovarian function suppression in premenopausal patients, and aromatase inhibitors cause estrogen deprivation in postmenopausal patients. These effects cause unbalance of bone metabolism, loss of bone density and increase in the incidence of fractures. Improvement of these bone-related adverse effects and careful follow-ups are needed for breast cancer patients.

The purpose was to investigate side effects of FEC100 treatment, particularly bone marrow suppression, nausea and vomiting.

Recently, it is reported that a omega-3 fatty acid-containing diet (Racol) enhances innate immunity and reduces mucosal damage in the small intestine during chemotherapy. The aim of this study is to examine the effects of a omega-3 fatty acid-containing diet (Racol) on the toxicity of chemoradiation therapy (CRT) for patients with esophageal cancers. Toxicity of CRT was evaluated in 10 patients who took Rakol at a maximum dose of 600 mL/day during CRT, compared with 10 patients who did not take Rakol. Regarding blood toxicity, the decrease of platelets did not differ between the former and the latter. However, the incidence of grade 2~4 neutropenia was lower in the former than in the latter (p=0.0043). With regard to gastrointestinal toxicity, the incidence of grade 2~4 diarrhea was also lower in the former than in the latter (p=0.0118). Moreover, the incidence of grade 2~4 stomatitis/pharyngitis tended to decrease in patients who took Rakol compared with those who did not (p=0.0812). The current results indicated that a omega-3 fatty acid-containing diet (Racol) may be beneficial to patients with esophageal cancers who receive CRT by reducing CRT toxicity.

Anemia is common in patients with cancer. The incidence and severity of anemia depend on the type and extent of the malignancy. Anemia may be the result of the malignancy itself, cancer treatment, blood losses, hemolysis or inflammatory cytokines associated with chronic disease. Anemia can have a profound impact on physical and psychosocial function and quality of life. However, in Japan, only iron supplementation and blood transfusion were available for the treatment of anemia with cancer. On the other hand, in Europe and America, erythropoietic agents such as erythropoietin and novel erythropoiesis stimulating protein (NESP) have been clinically used for anemia in patients with cancer.

Cisplatin, a simple inorganic compound, has been one of the leading antitumor drugs for near 30 years. However, cisplatin has several drawbacks such as toxicity and drug resistance. Therefore, much attention has been focused on the development of new platinum complexes with improved pharmacological properties and a broader spectrum of activity to tumors. The recent advance of research on the molecular mechanisms of drug action and the cellular mechanisms of the emergence of resistance to cisplatin assists the rational design of new classes of platinum antitumor drugs, though details of both mechanisms still remain elusive. Information on DNA binding mode of platinum complexes, recognition and repair of DNA damage is instructive. Since several not cis isomers but trans isomers and not neutral complexes but cation complexes have been found active in vitro and in vivo, the early empirical structure-activity relationships of cisplatin analogues should be reevaluated. The hypothesis that platinum complexes which bind to DNA in a different manner will have different pharmacological properties has been tested, and now cationic multi-nuclear complexes and even trans-platinum complexes comprise unique classes of antitumor platinum-based agents with chemical and biological properties different from cisplatin. These new type platinum complexes are often effective to acquired cisplatin resistant tumor cells. In conclusion, the following complexes appear to offer great potential as new antitumor agents: (1) Complexes with distinctively different DNA interaction modes from cisplatin, which may circumvent intrinsic and acquired resistance to cisplatin through eluding the vigilance of DNA repair systems and (2) complexes with different tissue distribution or mechanisms of membrane transport which may exhibit a different spectrum of activity.

Patients with cancer often take multiple medications. These medications may be directed at underlying neoplasms or at secondary symptoms. These chemotherapeutic agents may have other actions on the central nervous system. Accordingly the various mechanisms inducing neurotoxicity, especially headache is considered. Actually, when a patient with cancer feels new headache, we must consider not only the possibility of direct effects of existing cancer, but also the side effect of drugs used in chemotherapy. For the treatment of headache, firstly the history of the symptom must be evaluated. Then the physical and neurological condition of the patient is evaluated. Following this, the assessment of organic lesion should be done by using imaging methods or the other methods. Many antineoplastic drugs may induce headache. But in many cases, the pathophysiological mechanism of these drug-induced headaches is not full understood. We should collect more information about the character of the headache.

Various causes of cerebrovascular complications exist in patients with malignant tumor. The pathogenesis of thrombosis in malignancy is complex and it has not been completely clarified as yet. A hypercoagulable state in these patients occurs through several interactive processes between the cancer cells and the patient. Tumor cells can directly and indirectly enhance activation of coagulation cascade. Trousseau's syndrome is a paraneoplastic neurologic syndrome which is caused by remote effects of cancers. Tumor cells produce cytokines which promote coagulation and suppress anticoagulant activities, thereby causing stroke in cancer patients. Brain tends to be a target organ of stroke in the conditions of disseminated intravascular coagulopathy (DIC) in cancer patients. Nonbacterial thrombotic endocarditis (NBTE) is characterized by the presence of relatively acellular aggregates of fibrin and platelets attached to normal heart valves. NBTE can be found in DIC. Paradoxical embolism due to patent foramen ovale in patients with deep vein thrombosis is also one of the cause of cerebral infarction. Stroke can occur under various setting of cancer chemotherapy. Tamoxifen increases the risk of stroke in patients with breast cancer. In paticular, it has been reported that the combination of chemotherapy and tamoxifen for breast cancer patients frequently produces thrombotic episodes. Patients with head and neck cancer treated with local radiotherapy have a high risk of developing significant carotid stenosis, and an increased risk of stroke. Malignancy as a risk factor for stroke is becoming increasingly recognized by physicians caring for these patients. The probability of stroke occurring in an individual patient depends on several factors such as intrinsic medical problems, the type of cancer, the clinical stage, performance status, and the treatment modalities employed. Understanding these factors is important for stroke prevention and provision in this population.

Leucoencephalopathy caused by antineoplastic drugs was reviewed. This leucoencephalopathy primarily involved the cerebral white matter, caused by various anti-neoplastic drugs such as carmofur, fluorouracil, cytarabine, cisplatin, tegafur, methotrexate, tacrolimus, and interferon alfa. The interval between the time of drug administration and the onset of leucoencephalopathy varies among the drugs, depending on the kind of the drugs, their daily dosage, duration of the administration, and presence or absence of other combined treatments. This review primarily focused on carmofur-induced leucoencephaloathy, since this drug is developed and widely used in Japan against the carcinomas of the gastrointestinal tract and breast, and has caused leucoencephalopathy at the estimated incidence of 0.026% since 1982. The common symptoms of carmofur leucoencephalopaty were gait disturbance followed by dysarthria and dementia in that order of frequency, leading to coma in the advanced stage of the encephalopathy. EEG is the most sensitive test, but cranial CT and MRI tests are more specific, and MRI T2-weighted imaging is the most useful test, revealing symmetrical bilateral diffuse high intensity areas in the cerebral white matter. Intravenous high dose MTX has a strong tendency to cause leucoencephalopathy when combined with cranial radiation therapy. Reversible posterior leucoencephalopathy proposed by Hinchey et al. in 1996 has also been caused by some antineoplastic drugs. The most important treatment of the leucoencephalopathy caused by antineoplastic drugs is the immediate cessation of the causative drugs, followed by supportive therapy which included treatment to various complications and prevention of the decubitus and contractures of the joints.

Recently treatments of carcinoma are made great progres, therefore life period of patients with carcinoma are prolonged. But a neurotoxicity is one of the chemotheraphy side effects. Some anticancer drugs (cisplatin (CDDP), vincristine (VCR), paclitaxel (PTX), interferon, thalidomide etc) cause polyneuropathy, especially cisplatin neuropathy is unreversible damage. Therefore we should be careful to use cisplatin.

CPT-11 is activated by hydrolysis to SN-38 that is primarily inactivated through biotrans-formation into SN-38 glucuronide ( SN-38 G) by UGT1As. Tailoring chemotherapy based on the genetic profile of patients and tumor would increase efficacy and decrease toxicity for patients. The toxicities of CPT-11 have been reported to correlate with the polymorphism of the number of TA repeats in UGT1A1 gene because of its gene transcriptional efficiency. UGT1A1*28 was chosen as the candidate gene to be investigated as a predictor of severe toxicity. Other studies determining predictive markers of CPT-11 efficacy have been highly controversial.

Pharmacogenetics has been widely studied to predict the clinical outcome including response, survival, and toxicity in patients treated by fluoropyrimidines based on a candidate approach. Several "candidate" gene expressions or polymorphisms in 5-fluorouracil pathway have been selected and identified retrospectively to correlate closely with the clinical outcome in small patient cohorts. Because of the lack of prospective confirmation, these candidate genes have not yet been applied in clinical practice as the predictive biomarker. Further studies by the pathway approach which overview the entire 5-fluorouracil pathway and that by the global approach using array are warranted.

The accuracy of an individualized tumor response (ITR) assay in Japan was reportedly 74% (30th Annual Meeting of Japan Research Society for Appropriate Cancer Chemotherapy). Based upon the hypothesis according to which the appropriate adjuvant cancer chemotherapy will increase the survival outcome after surgery of advanced gastric cancer, we have clarified the usefulness of an ITR assay in evaluating the appropriate adjuvant chemotherapy for gastric cancer. While recent reports indicate the standard therapy for gastric cancer, the gastric cancer cohort includes responder and non-responder to adjuvant cancer chemotherapy. The ITR assay will be useful to differentiate the responder and nonresponder to cancer chemotherapy.

Various anticancer drug treatments have contributed to elongating survival of cancer patients. However, cancer often metastasizes and recurs in spite of anti-cancer drug treatment. It is important to control metastasis in order to achieve a favorable outcome. In this study, we confirmed that an expression of E-selectin in human umbilical vein endothelial cells (HUVEC) was stimulated by 5-FU, and that the expression of E-selectin was inhibited by cimetidine which was a H2 receptor antagonist.

In our hospital, beginning in April 2005, chemotherapy for non-curative advanced or recurrent gastric cancer was integrated, and 9 regimens including 6 combination therapies were prepared. First-line chemotherapy mainly focusing on TS-1 plus docetaxel combination therapy(S-1+DOC)was done. Second-line and subsequent chemotherapy treatments were chosen by the doctor in charge. 78.6% of second-line chemotherapy was monotherapy. Median survival time(MST)since first-line chemotherapy was 15.6 months, and 1-year survival rate since first-line chemotherapy was 65.0%. MST since the start of first-line S-1+DOC was over 16.4 months, and 1-year survival rate since this therapy start was 69.0%. The good results were ascribed to following: 1. good response rate(30.4%), prolonged time to progression(TTP)(6.1 months), and good control against adverse events at first-line chemotherapy; 2. good shift rate of second-line chemotherapy from the first-line one(82.4%); and 3. good disease control rate(78.6%), prolonged TTP(7.0 months), and good control against adverse events at second-line chemotherapy. In patients with peritoneal metastasis, however, despite the prolonged TTP of 8.7 months by first-line chemotherapy, MST since first-line chemotherapy was poor at 11.1 months. Thus, improvement of second-line or subsequent chemotherapy is warranted.

The ability of glucocorticoids (GCs) to kill lymphoid cells via a process called apoptosis has led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies. Since GC receptor(GR) is a ligand-dependent transcription factor, there should be genes mediating apoptosis among the ones whose expression is induced by GC. This review summarizes recent advances related to the molecular basis of GC-induced apoptosis, focusing on microarray analysis. Various groups of genes have been identified as candidate target genes of GR including the ones encoding Bcl-2 family proteins and calcineurin inhibitors. Although further investigation is required to determine the genes causally involved in GC-induced apoptosis, the studies described here will hopefully lead to more efficient treatments of lymphoid malignancies.

Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, suppress cell proliferation and induce apoptosis in various cancer cell lines. However, the effects of statins in head and neck carcinoma have not been reported. In this study, we investigated the mechanism by which fluvastatin induces apoptosis in HSC-3 cells. An increase in caspase-3 activity was observed. The apoptosis induced by fluvastatin was inhibited by the addition of geranylgeranyl pyrophosphate (GGPP) to the cell culture. When we examined the survival signals at the time of apoptotic induction, we also found that fluvastatin had caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Moreover, we also found that U0126, a MEK1/2 inhibitor, induces apoptosis in HSC-3 cells. These results suggested that fluvastatin induces apoptosis by inhibiting GGPP biosynthesis and consequently decreasing the level of phosphorylated ERK1/2. The results of this study also indicate that fluvastatin may be used as an anticancer agent for tongue carcinoma.

We propose an improved method to measure urinary D-glucaric acid (GA), which might be of value as an indirect index of the activity of cytochrome P450 (CYP). This method was about 20 times more sensitive than existing methods. Beer's law was obeyed in the concentration range 5.5-66 ng ml(-1) for GA, with the effective molar absorptivity at 533 nm and the relative standard deviation being 9.1 x 10(5) dm(3) mol(-1) cm(-1) and 0.69% (n = 6), respectively. In addition, we introduced the correction value {GA/Cr ratio x10} of urinary GA by measuring urinary creatinine (Cr) at the same time. Based on the proposed method, the GA and Cr values in spot urines of healthy persons and cancer patients were subsequently measured and the correction values of both groups subjected to comparison. As a result, a statistically significant difference was recognized between the two groups.

Prostate cancer is the most common non-cutaneous malignant neoplasm in men in Western countries. In Japan, the number of afflicted men has been increasing although it is still low compared with Western countries. One of the most important problems in prostate cancer patients is treatment for hormone-refractory prostate cancer (HRPC). Although docetaxel is considered as a first-line chemotherapeutic option in patients with HRPC in the USA, it is still necessary to search and develop new drugs. Spheroid culture models have an invaluable role in tumor biology or drug screening. Characteristics of cancer cells in three-dimensional (3D) culture, especially spheroid culture, differ dramatically from those in two-dimensional (2D) culture. Spheroid culture models appear to be an ideal tool, however, their models have not been incorporated in drug screening. In this article, we demonstrate characterization of prostate cancer spheroids including chemo-resistance compared with 2D culture and xenograft models. Prostate cancer cells except PC-3 formed E-cadherin-mediated spheroids. An immunocytochemical analysis of the spheroids revealed that cells showing Ki-67 were localized in the peripheral layer and the intermediate zone cells showed p27 and poly (ADP-ribose) polymerase-1 (PARP-1), suggesting quiescent cell character. Prostate cancer cells acquired resistance to most agents when grown as spheroids, but not to all of the anticancer agents tested. This article also attempts to provide up-to-date information about spheroids, especially quiescent cells as therapeutic targets and the involvement of genetics and epigenetics in forming spheroids.