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GroundBIRD is a ground-based experiment for the precise observation of the polarization of the cosmic microwave background (CMB). To achieve high sensitivity at large angular scale, we adopt three features in this experiment: fast rotation scanning, microwave kinetic inductance detector (MKID) and cold optics. The rotation scanning strategy has the advantage to suppress $1/f$ noise. It also provides a large sky coverage of 40\%, which corresponds to the large angular scales of $l \sim 6$. This allows us to constrain the tensor-to-scalar ratio by using low $l$ B-mode spectrum. The focal plane consists of 7 MKID arrays for two target frequencies, 145 GHz and 220 GHz band. There are 161 pixels in total, of which 138 are for 144 GHz and 23 are for 220 GHz. This array is currently under development and the prototype will soon be evaluated in telescope. The GroundBIRD telescope will observe the CMB at the Teide observatory. The telescope was moved from Japan to Tenerife and is now under test. We present the status and plan of the GroundBIRD experiment., 7 pages, 5 figures, LTD18 proceeding, Published in JLTP

GroundBIRD is a millimeter-wave telescope to observe the polarization patterns of the cosmic microwave background (CMB). The target science topics are primordial gravitational waves from cosmic inflation and reionization optical depth. Therefore, this telescope is designed to achieve the highest sensitivity at large angular scales, e = 6 - 300. For wide sky observations (~40% full-sky), scanning at a high rotation speed (120°/s) is important to remove atmospheric fluctuations. Microwave kinetic inductance detector (MKID) is utilized with the fast GroundBIRD rotation since its good time response. We have started the commissioning run at the Teide Observatory in the Canary Islands. We report the performance of the telescope, receiver, and data acquisition system, including cooling achievements, observations of astronomical objects, and observations taken during several days ahead of our main survey observations.

Microwave kinetic inductance detectors have a variety of potential applications in astronomical observations. We built a data acquisition system for kinetic inductance detectors combining a dedicated analog board and a commercially available digital board to meet the requirements of astronomical measurements, such as observation of the cosmic microwave background. This paper reports the status of the development of the data acquisition system. We have already achieved simultaneous readout through 120 channels using a direct down-conversion method to decode the signal. A variety of software has been developed and tested using the functionalities of the system and actual detectors.

The GroundBIRD telescope aims to detect B-mode polarization of the cosmic microwave background radiation using the kinetic inductance detector array as a polarimeter. For the readout of the signal from detector array, we have developed a frequency division multiplexing readout system based on a digital down converter method. These techniques in general have the leakage problems caused by the crosstalks. The window function was applied in the field programmable gate arrays to mitigate the effect of these problems and tested it in algorithm level.

The cosmic microwave background (CMB) radiation is an afterglow of the Big Bang. It contains the crucial keys to understand the beginning of the universe. In particular, the odd-parity patterns of CMB polarization, B-modes, at more than degree-scale, are the best probe to detect primordial gravitational waves at the cosmic inflation. The GroundBIRD experiment aims to detect this large angular scale patterns from the ground. The experiment employs novel techniques; a high-speed rotational scanning system (20 revolution-per-minutes) with cold optics below 4K, and microwave kinetic inductance detectors (MKIDs) as the focal plane detectors. The fast scanning modulation is a crucial characteristic in our observation strategy to mitigate effects of the atmospheric fluctuation. The telescope rotates and scans the sky along the azimuth at the elevation angle of 60 degrees at Teide observatory in the Canary Islands. It allows us to measure CMB polarization patterns at a wide multipole range, 6 < \ell < 300, i.e. aiming to catch the reionization bump. We have developed a telescope mount with 3-axis rotation mechanism (azimuth, elevation, and boresight). We are evaluating the vibration at the focal plane position with rotating the telescope mount. The focal plane consists of seven hexagonal corrugated horn coupled MKIDs array: six hexagon units are for 145 GHz band (55 pixels/unit), and one unit is for 220 GHz band (112 pixels). Each pixel consists of a corrugated horn, a planner OMT, millimeter wave circuits for transmission of dual-polarization signals with the suppression of crosstalk modes, and two MKIDs for each polarization. Magnetic shields are also mounted so as to suppress the external magnetic fields. Trapped magnetic fields inside of the superconducting materials decrease the performance of the MKID. The geomagnetism is the static and large magnetic fields. The telescope motion makes modulation of the geomagnetism as well as the modulation of CMB signals. Therefore, we need careful evaluation associating with the telescope rotation. By using a small evaluation system with modulated magnetic fields, we understand impacts the magnetic shield as well as responses of the MKID for the modulated magnetic field. We design the shield based on them. In this presentation, we will report an evaluation of detector responses on the high-speed rotating system along the azimuth. We will also show demonstrations of our own readout electronics which is well matching with the rapid scan modulation strategy.

The kinetic inductance detector (KID) is a cutting-edge superconducting detector. The number of KID developers is growing. Most of them have switched from their previous study to superconducting technologies. Therefore, infrastructures for the fabrication of KIDs and cooling systems for their tests have already been established. However, readout electronics have to be newly prepared. Neither a commercial system nor low-cost standard electronics are available despite various attempts to create a standard one. We suggest the use of RedPitaya as readout electronics for the initial step of KID development, which is low cost ( $$\approx $$ 400 USD) and easy to set up. The RedPitaya consists of an all-programmable FPGA-CPU module and a dual-channel 14 bit DAC (ADC) to generate (measure) fast analog signals with 125 MSpS. Each port can be synchronized in-phase or quadrature-phase, and functions for generating and sampling analog signal are prepared. It is straightforward to construct vector network analyzer-like logic by using a combination of these default functions. Up-conversion and down-conversion of its frequency range are also possible by using commercial equipment, i.e., mixers, couplers, and a local oscillator. We implemented direct down-conversion logic on the RedPitaya, and successfully demonstrated KID signal measurements.

Precise measurements of polarization patterns in cosmic microwave background (CMB) provide deep knowledge about the begin of the Universe. The GroundBIRD experiment aims to measure the CMB polarization by using microwave kinetic inductance detector (MKID) arrays. The MKID is suited to multiplexing. One of our requirements is a MUX factor (the number of readout channels for a single wire pair) of at least 100. If we make frequency combs of the MKIDs with 2-MHz spacing, a bandwidth of 200 MHz satisfies 100 MUX. The analog electronics must consist of an analog-to-digital converter (ADC), digital-to-analog converter (DAC), and local oscillator. We developed our own analog electronics board “RHEA.” Two outputs/inputs of DAC/ADC with a 200-MHz clock provide an effective bandwidth of 200 MHz. The RHEA allows us to measure both the amplitude and phase responses of each MKID simultaneously. These data are continuously sampled at a high rate (e.g., 1 kSPS) and with no dead time. We achieved 12 and 14 bits resolution for ADC and DAC, respectively. This corresponds to achieve that our electronics achieved low noise: 1/1000 compared with the detector noise. We also achieved low power consumption compared with that of other electronics development for other experiments. Another important feature is that the board is completely separated from the digital part. Each user can choose their preferred field-programmable array. With the combination of the Kintex-7 evaluation kit from Xilinx, we demonstrated readout of MKID response.

Cosmic microwave background (CMB) is an important source of information about the origin of our universe. In particular, odd-parity large angular scale patterns in the CMB polarization, the primordial B-modes, are strong evidence for an inflationary universe, related to the accelerating expansion of the metric. We are developing a unique telescope, GroundBIRD, to take CMB polarization measurements. The telescope combines novel techniques: high-speed rotation scanning, cold optics, and microwave kinetic inductance detectors (MKIDs). We evaluated the response of MKIDs on the rotation stage. Method of shielding from the geo-magnetic field is established. We have also developed a receiver cryostat. We are able to maintain a sufficient cold status for observations on the optical configuration. We plan to start commissioning the system by observing CMB in Japan in 2015–2016. We will then deploy GroundBIRD in the Canary Islands for further scientific observations.

Polarized patterns in the cosmic microwave background (CMB) radiation contains rich knowledge for early stage of the universe. In particular their odd-parity patterns at large angular scale (> 1°), primordial B-modes, are smoking-gun evidence for the cosmic inflation. The GroundBIRD experiment aims to detect these B-modes with a ground-based apparatus that includes several novel devices: a high-speed rotational scan system, cold optics, and microwave kinetic inductance detectors (MKIDs). We plan to start observations in the Canary Islands in 2017. In this paper, we present the status of the development of our instruments. We established an environment that allows operation of our MKIDs in an optical configuration, in which the MKIDs observe radiations from the outside of the telescope aperture. We have also constructed MKID prototypes, and we are testing them in the optical configuration.

Our understanding of physics at very early Universe, as early as 10−35 s after the Big Bang, relies on the scenario known as the inflationary cosmology. Inflation predicts a particular polarization pattern in the cosmic microwave background, known as the B-mode yet the strength of such polarization pattern is extremely weak. To search for the B-mode of the polarization in the cosmic microwave background, we are constructing an off-axis rotating telescope to mitigate systematic effects as well as to maximize the sky coverage of the observation. We will discuss the present status of the GroundBIRD telescope.

We present the mission design of LiteBIRD, a next generation satellite for the study of B-mode polarization and inflation from cosmic microwave background radiation (CMB) detection. The science goal of LiteBIRD is to measure the CMB polarization with the sensitivity of δr = 0:001, and this allows testing the major single-field slow-roll inflation models experimentally. The LiteBIRD instrumental design is purely driven to achieve this goal. At the earlier stage of the mission design, several key instrumental specifications, e.g. observing band, optical system, scan strategy, and orbit, need to be defined in order to process the rest of the detailed design. We have gone through the feasibility studies for these items in order to understand the tradeoffs between the requirements from the science goal and the compatibilities with a satellite bus system. We describe the overview of LiteBIRD and discuss the tradeoffs among the choices of scientific instrumental specifications and strategies. The first round of feasibility studies will be completed by the end of year 2014 to be ready for the mission definition review and the target launch date is in early 2020s.

We developed a cryogenic system on a rotating table that achieves sub-Kelvin conditions. The cryogenic system consists of a helium sorption cooler and a pulse tube cooler in a cryostat mounted on a rotating table. Two rotary-joint connectors for electricity and helium gas circulation enable the coolers to be operated and maintained with ease. We performed cool-down tests under a condition of continuous rotation at 20 rpm. We obtained a temperature of 0.23 K with a holding time of more than 24 hours, thus complying with catalog specifications. We monitored the system's performance for four weeks; two weeks with and without rotation. A few-percent difference in conditions was observed between these two states. Most applications can tolerate such a slight difference. The technology developed is useful for various scientific applications requiring sub-Kelvin conditions on rotating platforms., 3pages, 4 figures, to appear in Review of Scientific Instruments

The fluorinated pyrimidine nucleoside, 5′-deoxy-5-fluorouridine (5′-dFUrd) has been shown to effectively attenuate the progress of cachexia in the murine adenocarcinomas MAC16 and colon 26 as well as in the human uterine cervical carcinoma xenograft, Yumoto. Although concomitant inhibition of tumour growth was observed in all three models this was not sufficient to account for the preservation of body weight. An attempt has been made to correlate the anti-cachectic activity of 5′-dFUrd with the presence of a tumour produced proteolysis-inducing factor (PIF), thought to be responsible for the development of cachexia in the MAC16 model. Two variants of colon 26 adenocarcinoma were employed, clone 20 which produces profound cachexia, and clone 5 which produces no change in body weight in recipient animals. Mice bearing the colon 26, clone 20 variant showed evidence for the presence of PIF in tumour, serum and urine, while there was no evidence for the presence of PIF in tumour or body fluids of mice bearing the clone 5 tumours. Treatment of animals bearing the clone 20 variant with 5′-dF Urd led to the disappearance of PIF from the tumour, serum and urine concomitant with the attenuation of the development of cachexia. The human cervical carcinoma, Yumoto, which also induced cachexia in recipiant animals, showed expression of PIF in tumour, serum and urine in control and vehicle-treated mice, but was absent in mice treated with 5′-dFUrd. Thus in these experimental models cachexia appears to be correlated with the presence of PIF. © 2000 Cancer Research Campaign

In the field of radiowave detection, enlarging the receiver aperture to enhance the amount of light detected is essential for greater scientific achievements. One challenge in using radio transmittable apertures is keeping the detectors cool. This is because transparency to thermal radiation above the radio frequency range increases the thermal load. A technology that maintains cold conditions while allowing larger apertures has been long-awaited. We propose radio-transparent multi-layer insulation (RT-MLI), composed from a set of stacked insulating layers. The insulator is transparent to radio frequencies, but not transparent to infrared radiation. The basic idea for cooling is similar to conventional multi-layer insulation. It leads to a reduction in thermal radiation while maintaining a uniform surface temperature. The advantage of this technique over other filter types is that no thermal links are required. As insulator material, we used foamed polystyrene; its low index of refraction makes an anti-reflection coating unnecessary. We measured the basic performance of RT-MLI to confirm that thermal loads are lowered with more layers. We also confirmed that our RT-MLI has high transmittance to radiowaves, but blocks infrared radiation. For example, RT-MLI with 12 layers has a transmittance greater than 95% (lower than 1%) below 200 GHz (above 4 THz). We demonstrated its effects in a system with absorptive-type filters, where aperture diameters were 200 mm. Low temperatures were successfully maintained for the filters. We conclude that this technology significantly enhances the cooling of radiowave receivers, and is particularly suitable for large-aperture systems. This technology is expected to be applicable to various fields, including radio astronomy, geo-environmental assessment, and radar systems., 7 pages, 8 figures, to appear in Review of Scientific Instruments

Odd-parity patterns in the cosmic microwave background (CMB) polarization, B -modes, could provide important cosmological information. Detection of the primordial B -mode power at a large angular scale would be a smoking gun signature of the inflationary universe. In particular, detecting a reionization bump (at a multipole of ≤ 10) should be a clear evidence of it. GroundBIRD is designed to detect the B -mode signal at this large angular scale from the ground. We will use superconducting detector arrays with small telescope that will also be cooled down to 4K. Therefore, the basic design can be extended to a satellite experiment. GroundBIRD employs a high-speed (20 rpm) rotation scan instead of the usual left–right azimuthal scan; this allows us to maintain a high-speed scan without any deceleration, resulting in a significant expansion of the scan range to 60° without any effect of the detector 1/ f noise. Our target is measuring the CMB polarization power in a multipole ( l ) range of 6 ≤ l ≤ 300. We plan to start commissioning the instruments in Japan in early 2014; they will then be moved to the Atacama Desert in Chile for scientific observations.

The large-scale cryogenic gravitational wave telescope (LCGT) is the future project of the Japanese gravitational wave group. Two sets of 3 km arm length laser interferometric gravitational wave detectors will be built in a tunnel of Kamioka mine in Japan. LCGT will detect chirp waves from binary neutron star coalescence at 240 Mpc away with a S/N of 10. The expected number of detectable events in a year is two or three. To achieve the required sensitivity, several advanced techniques will be employed such as a low-frequency vibration-isolation system, a suspension point interferometer, cryogenic mirrors, a resonant side band extraction method, a high-power laser system and so on. We hope that the beginning of the project will be in 2005 and the observations will start in 2009.

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd) to 5-fluorouracil (5-FUra) in tumors. We observed previously that several cytokines and cytostatics up-regulated dThdPase expression and consequently enhanced the efficacy of capecitabine and 5'-dFUrd. In the present study, we found that X-ray irradiation also up-regulated dThdPase expression in several human cancer xenografts. A single-dose local irradiation at 5 Gy increased dThdPase levels by up to 13-fold at 9 days after the irradiation. Whole-body irradiation also up-regulated dThdPase in a tumor, but it did not increase the enzyme level in the liver. We also observed that the irradiation increased the levels of human tumor necrosis factor alpha (TNF-alpha), which is an up-regulator of dThdPase, prior to the dThdPase up-regulation. These results indicate that X-ray irradiation might increase dThdPase levels indirectly through the human TNF-alpha in the tumor tissue. In the WiDr colon and MX-1 mammary human cancer xenograft models, the combination of a single local X-ray irradiation with either capecitabine or 5'-dFUrd was much more effective than either radiation or chemotherapy alone. In contrast, treatment with X-ray irradiation and 5-FUra in combination showed no clear additive effects. Combined modality treatment of cancer patients with cape-citabine and X-ray irradiation would have greater potential usefulness than conventional radiochemotherapy with 5-FUra.

Murine colon 26 carcinoma growing at either subcutaneous (s.c.) or intramuscular (i.m.) inoculation sites causes cachexia in mice. Such animals show extensive loss of body weight, wasting of the muscle and adipose tissues, hypoglycaemia, and hypercalcaemia, even when the tumour weight comprises only about 1.9% of carcass weight. In contrast, the same tumour when inoculated into the liver does not cause any sign of tumour-related cachexia even when the tumour becomes much larger (6.6% of carcass weight). Interleukin 6 (IL-6), a mediator associated with cachexia in this tumour model, is detected at high levels both in the tumour tissues and in the circulating blood of mice bearing colon 26 tumour at the s.c. inoculation site. In contrast, only minute levels of IL-6 are detected in the tumour grown in the liver. The colon 26 tumour grown in the liver does not lose its ability to cause cachexia, because the tumour when re-inoculated s.c. is able to cause extensive weight loss and produce IL-6 as did the original colon 26 cell line. Histological studies revealed differences in the composition of tumour tissues: the tumours grown in the subcutis consist of many polygonal tumour cells, extended-intercellular space, and high vascular density, whereas those grown in the liver consist of spindle-shaped tumour cells. Thus, the environment where tumour cells grow would be a critical factor in determining the cachectic phenotype of cancer cells, including their ability to produce IL-6. 1999 Cancer Research Campaign

2'-Deoxy-2'-methylidenecytidine (DMDC) is a new 2'-deoxycytidine (dCyd) antimetabolite. The present study compared its antitumor activities with those of 2',2'-difluorodeoxy-cytidine (gemcitabine) in 15 human cancer xenograft models. DMDC was highly resistant to cytidine (Cyd) deaminase, which deaminates the dCyd analogues to inactive molecules, whereas gemcitabine was susceptible to the enzyme. Given p.o., high antitumor activity with therapeutic index of more than 10 was found with DMDC in 7 of 15 xenograft lines. In contrast, gemcitabine given i.v. or p.o. was highly effective in 4 of 15 human cancer xenograft lines. The antitumor spectrum of these compounds was quite different, although their molecular targets are reported to be similar. DMDC was highly effective in tumors with higher levels of Cyd deaminase activity, whereas it showed only slight activity in those with lower levels of Cyd deaminase. In contrast, gemcitabine appeared to be less effective in tumors with high levels of Cyd deaminase. We also investigated the correlation with the susceptibility to the two dCyd antimetabolites and dCyd kinase activity in tumors, but none was observed. Cyd deaminase activity was found to be high in tumor tissues from various types of human cancers thus far tested, such as colorectal cancer and non-small cell lung cancer. Such cancer types or individual patients who have tumors with high activity of the enzyme may be targets for DMDC therapy.

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite [5'-deoxy-5-fluorouridine (5'-dFUrd)] to 5-fluorouracil in tumors. We have tried to identify the best partners of capecitabine in combination therapy, such as dThdPase up-regulators, which may enhance the efficacy of this compound. Among various cytostatics studied with the WiDr human colon cancer xenograft model, Taxol, Taxotere, and mitomycin C greatly increased levels of human dThdPase in tumors, and cyclophosphamide slightly increased the enzyme level. These cytostatics simultaneously increased the levels of human tumor necrosis factor alpha (TNFalpha), which is an up-regulator of dThdPase. In cultures of the WiDr cells, however, Taxol did not up-regulate TNFalpha to a detectable level and only slightly enhanced levels of dThdPase. These results suggest that Taxol might indirectly elevate TNFalpha in tumor cells, which in turn up-regulated dThdPase in the tumor cells in the WiDr cancer xenograft. In the combination therapy, the efficacy of Taxol and Taxotere with either capecitabine or 5'-dFUrd was more than just additive. In contrast, Taxol and either 5-fluorouracil or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Taxol and Taxotere might enhance the efficacy of capecitabine and 5'-dFUrd, probably by modulating dThdPase activity in tumor tissues.

We showed that the efficacy of the new 2'-deoxycytidine (2'-dCyd) analogue antimetabolite 2'-deoxy-2'-methylidenecytidine (DMDC) correlates well with tumor levels of cytidine (Cyd) deaminase in human cancer xenograft models. DMDC was highly effective in tumors with higher levels of Cyd deaminase, whereas lower levels yielded only slight activity. In contrast, gemcitabine (2',2'-difluorodeoxycytidine), which has action mechanisms similar to those of DMDC, is only slightly active in tumors with higher levels of the enzyme. In the present study, we investigated the roles of Cyd deaminase in the antitumor activity of the two 2'-dCyd antimetabolites in 13 human cancer cell lines. Tetrahydrouridine, an inhibitor of Cyd deaminase, reduced the antiproliferative activity of DMDC (P = 0.0015). Furthermore, tumor cells transfected with the gene of human Cyd deaminase become more susceptible to DMDC both in vitro and in vivo. These results indicate that Cyd deaminase is indeed essential for the activity of DMDC. In contrast, the antiproliferative activity of gemcitabine was increased to some extent by tetrahydrouridine (P = 0.0277), particularly in tumor cell lines with higher levels of Cyd deaminase. This suggests that higher levels of Cyd deaminase may inactivate gemcitabine. Among nucleosides and deoxynucleosides tested, only dCyd, a natural substrate of both Cyd deaminase and dCyd kinase, suppressed the antiproliferative activity of DMDC by up to 150-fold. Because the Vmax/Km of DMDC for dCyd kinase was 8-fold lower than that for dCyd, the activation of DMDC to DMDC monophosphate (DMDCMP) by dCyd kinase might be competitively inhibited by dCyd. In addition, the dCyd concentrations in human cancer xenografts were inversely correlated with levels of Cyd deaminase activity. It is therefore suggested that higher levels of Cyd deaminase reduce the intrinsic cellular concentrations of dCyd in tumors, resulting in efficient activation of DMDC to DMDCMP by dCyd kinase. These results indicate that the efficacy of DMDC may be predicted by measuring the activity of Cyd deaminase in tumor tissues before treatment starts and that DMDC may be exploited in a new treatment modality: tumor enzyme-driven cancer chemotherapy.

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a new fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FUra) selectively in tumors through the intermediate metabolite 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine). 5'-dFUrd is metabolized to 5-FUra by thymidine phosphorylase (dThdPase) located in high levels in various types of solid tumors from patients, whereas 5-FUra generated is catabolized to dihydrofluorouracil by dihydropyrimidine dehydrogenase (DPD). The present study investigated whether the efficacy of capecitabine and its intermediate metabolite 5'-dFUrd correlates with levels of these enzymes in various human cancer xenograft models. Capecitabine and 5'-dFUrd were highly effective and inhibited tumor growth by more than 50% in 18 of 24 xenograft lines (75%) and 15 of 24 xenograft lines (63%), respectively, whereas 5-FUra and a mixture of tegafur and uracil were effective only in 1 of 24 (4.2%) and 5 of 24 (21%), respectively. The efficacy of capecitabine correlated with dThdPase activity. However, capecitabine was effective even in tumors with lower levels of dThdPase if DPD levels were also lower. In contrast, it was not as effective even in tumors with sufficient levels of dThdPase if DPD levels were very high. The efficacy of capecitabine consequently correlated very well with and depended on the ratio of these two enzymes in tumors. These results indicate that capecitabine might exert its efficacy through 5-FUra generated in tumor tissues but not through that generated in normal organs. On the other hand, there was no correlation between the efficacy of a mixture of tegafur and uracil and these enzyme activities in tumors. The efficacy of capecitabine would be optimized by selecting patients who have tumors with a high ratio of dThdPase to DPD activities.

Efficacy of long-term combination chemotherapy of cyclophosphamide (CPA) and 5'-deoxy-5-fluorouridine (5'-DFUR), both of which have been widely used as chemotherapeutics against breast cancer patients, was examined in a mammary tumor xenograft model, MX-1. 5'-DFUR suppressed the tumor growth over a long period and prolonged the survival, although it did not reduce the initial tumor burden, CPA induced the disappearance of the tumor burden temporarily. However, CPA became inaffective despite continuation of treatment, and induced the recurrence of the tumor. The combination of these two drugs dramatically reduced the tumor burden, and suppressed the recurrence of the tumor over a long period. The tumor recurring during CPA monotherapy was resistant to CPA but susceptible to 5'-DFUR, which could be a reason for the long-lasting activity of the combination therapy. These results indicate that CPA and 5'-DFUR monotherapies have different modes of antitumor activities in the long-term therapy model, and that these drugs in combination would have better therapeutic advantage than each drug given individually.

A human tumor xenograft model for cancer cachexia was established by growing a uterine cervical carcinoma, Yumoto, in nude mice. The tumor transplanted into the mice induced severe body weight loss (30% of body weight) when the tumor weight was only 1 g. In addition, other indicators for cachexia, such as adipose tissue and muscle wasting and hypoglycemia, were also observed in the tumor-bearing mice, suggesting that this is a proper model for experimental cachexia induced by a human tumor. We then examined the association of this model with various cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1alpha, IL-1beta, IFN-gamma, IL-6, and leukemia inhibitory factor, and identified human IL-6, which was produced by the tumor cells, as a mediator of cachexia. A neutralizing antibody against hIL-6 administered to the mice after the development of cachexia symptoms significantly improved body weight loss, adipose tissue wasting, hypoglycemia, acute phase reaction, and leukocytosis, although it did not suppress the tumor growth. These results demonstrate that the hIL-6 produced by the tumor cells is an essential mediator of the cachexia induction in this model.

The synthesis of Ph-SiO2 film containing Qn-BOC latent pigment using the sol-gel method and the formation of thin film using laser irradiation have been investigated. The film is useful for a wavelength selective absorption film for displays and optical disk. Newly developed film formation technique using latent pigment and laser irradiation gives the excellent film having high transparency, excellent absorption characteristics and high durability. And also, this process is low cost process due to high speed film formation.

Antitumor activities of cytostatics such as 5-FU, 5'-DFUR, cyclophosphamide (CPA), ACNU, CDDP, mitomycin C (MMC) and doxorubicin (DXR) were compared in mice bearing four different murine-tumor models at two different stages of the tumor growth. All cytostatics tested suppressed the tumor growth in most of the four tumors, colon 26 carcinoma, UV 2237 fibrosarcoma, Ehrlich carcinoma and Meth A fibrosarcoma, when the tumor sizes were small (early transplant). When given to mice bearing advanced tumors, 5-FU, CDDP, MMC and DXR were effective only at the higher doses, showing toxicity. In contrast, 5'-DFUR was equally effective against both most of early and advanced tumors except for advanced Meth A against which higher doses of 5'-DFUR were needed. CPA and ACNU equally suppressed the growth of early transplant and advanced tumors of Meth A, although higher doses were needed against advanced tumors of three others. 5'-DFUR was also effective against tumor cachexia (colon 26) and spontaneous metastasis (Lewis lung carcinoma), which are characteristically observed in mice bearing advanced tumors. CPA also showed an anticachectic activity, though the activity was weaker than that of 5'-DFUR. These results suggest that 5'-DFUR and CPA can be used in both intensive and adjuvant chemotherapies.

Fluorinated pyrimidines given orally were examined for their antitumor activity with 11 human cancer xenograft models (4 bladder, 4 cervical and 3 ovarian cancers). The drugs were evaluated to be effective when they inhibited tumor growth over 58%. UFT was not effective against all of 11 cancer xenografts tested. 5-Fluorouracil (5-FU) was effective against only one bladder cancer xenograft among 6 cancer xenografts tested. On the other hand, 5'-deoxy-5-fluorouridine (5'-DFUR) was effective against one bladder, 3 cervical and one ovarian cancer xenografts. The Antitumor activity of 5'-DFUR was correlated with the enzyme activity of pyrimidine nucleoside phosphorylase, which is an essential enzyme for phosphorolysis of 5'-DFUR to 5-FU.

Murine colon 26 adenocarcinoma causes a progressive weight loss and physiological changes associated with cachexia when it grows to a certain size. By the use of this tumor model several types of cytostatics were examined for their ability to alleviate cachexia. Among them, 5'-deoxy-5-fluorouridine could reverse a progressive weight loss and improve hypoglycemia, hyperglucocorticism, and hepatic malfunctions, as well as inhibiting the tumor growth. Cyclophosphamide, nimustine, and 2'-deoxy-5-fluorouridine were only slightly effective in reversing the wasting, while 5-fluorouracil, tegafur, mitomycin C, cis-platinum, and doxorubicin were not active. Within 3 days after 5'-deoxy-5-fluorouridine was administered to cachectic mice with large tumor burdens, the wasting was immediately reversed even at doses in which there was increase or no significant reduction in tumor growth. These results indicate that the anticachectic activity of 5'-deoxy-5-fluorouridine is independent of its antiproliferative activity.

The present study investigates a tumor model for cachectic mice. Among various murine transplantable tumors, used for assessing cytostatics, we identified colon 26 adenocarcinoma (colon 26) as capable of causing cachexia. Fifteen days after inoculation, the tumor grew to about 6% of the body weight causing substantial carcass weight loss of 3.4 g (14.5% of the carcass weight). When the tumor size was 2.7 g at 3 weeks after the inoculation, the carcass weight was 12 g less than the age-matched control. The tumor continued to grow while the mice maintained this weight, surviving for an average of 45 days. This extensive weight loss was essentially the wasting of adipose and muscle tissues. Hypoglycemia and hypercorticism occurred during the time of the weight loss. In addition, the colon 26 caused disorders of hepatic functions: the concentration of acute phase proteins in serum increased; the number of hepatic glucocorticoid-cytosol receptors decreased; and activities of hepatic catalase and drug-metabolizing enzymes decreased. On the other hand, noncachectic mice with Meth A fibrosarcoma gained weight, which was somewhat less than the control, and had neither hypoglycemia nor hypercorticism, although some mild disorders of hepatic functions were found. Mice bearing colon 26 is an appropriate model for elucidating the mechanism that causes cachexia.

Modes of action of five antirhinovirus agents were compared. Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 were active preferentially against human rhinovirus. Serotypes of the virus varied in their susceptibility to these three agents, whereas Ro 09-0179 and enviroxime showed activity against all the serotypes of the virus tested to date. Ro 09-0410, RMI-15,731, and 4',6-dichloroflavan inactivated the virus directly, although 4',6-dichloroflavan did so only slightly. Inactivation by 4',6-dichloroflavan and RMI-15,731 was associated with the binding of the agents to the virus, since the infectivity, reduced by exposure to the agents, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]Ro 09-0410 to human rhinovirus type 2 was inhibited by unlabeled Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 but not by Ro 09-0179 or enviroxime. Furthermore, subtypes resistant to both 4',6-dichloroflavan and RMI-15,731 showed cross-resistance to Ro 09-0410 and vice versa. On the other hand, sublines resistant to these three agents were not cross-resistant to Ro 09-0179 or enviroxime. These results indicate (i) that Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 exert their activities through the same mode of action, namely, binding to or interaction with some specific site on the viral capsid protein, and (ii) that the binding or interaction sites for these three agents are either the same or very close to each other.

Ro 09-0179 (4',5-dihydroxy-3,3',7-trimethoxyflavone), isolated from a Chinese medicinal herb, was found to have potent antiviral activity. It selectively inhibited the replication of human picornaviruses, such as rhinoviruses and coxsackieviruses in tissue culture, but not other DNA and RNA viruses. Ro 09-0298 (4',5-diacetyloxy-3,3',7-trimethoxyflavone), an orally active derivative of Ro 09-0179, prevented coxsackievirus (B1) infection in mice. The critical time for the inhibition of rhinovirus replication by Ro 09-0179 was 2 to 4 h after virus adsorption, i.e., in the early stages of virus replication. It markedly inhibited coxsackievirus and rhinovirus RNA synthesis in infected HeLa cells, but not in a cell-free system using the RNA polymerase complex isolated from the infected cells. In the infected cells, the RNA polymerase complex was not formed in the presence of Ro 09-0179. Therefore, it is suggested that Ro 09-0179 interferes with some process of viral replication which occurs between viral uncoating and the initiation of viral RNA synthesis.

Antitumor activity and the toxicities of 5-fluorouracil (FUra) and its depot form derivatives with different mechanisms such as 5'-DFUR, tegafur and UFT, were compared in mice, and the therapeutic indices were measured. 5'-DFUR was less toxic to immune organs and the functions than those by other fluorinated pyrimidines. The therapeutic indices of 5'-DFUR obtained by using parameters of particular side effects, reduction of the number of GM-CFU in the bone marrow, shrinkage of the thymus, functional disorders in the immune systems, were several times higher than those of tegafur and UFT. On the other hand, there were no marked differences in the intestinal toxicities among the compounds. 5'-DFUR was only about two times less toxic on the intestinal tract than tegafur and UFT when the incidence-of diarrhea and damage to the duodenum were compared. These studies suggest that the difference in the mechanisms converting to FUra is a result of the toxicities causing different extent.

5'-Deoxy-5-fluorouridine (5'-DFUR) was parenterally and orally effective on various transplantable tumors and its activity was better than that of other fluorinated pyrimidines. However, like 5-fluorouracil and 2'-deoxy-5-fluorouridine (FUdR), 5'-DFUR was ineffective on L1210 leukemia resistant to 5-fluorouracil, suggesting that it would exert its antitumor activity through converted 5-fluorouracil. In tissue culture, 5'-DFUR inhibited the growth of various tumor cells similarly to ther fluorinated pyrimidines. However, 5'-DFUR was unique in that uridine completely reversed its inhibitory effect. Enzymological study clarified that uridine inhibited the conversion of 5'-DFUR to 5-fluorouracil by a uridine phosphorylase, in parallel to its reverse effect on cell growth inhibition by 5'-DFUR. Furthermore, a subline of L1210 leukemia resistant to 5'-DFUR but not to 5-fluorouracil was found to lack the uridine phosphorylase. These results indicate that 5'-DFUR is a depot form of 5-fluorouracil which can be promptly activated by uridine phosphorylase. In addition, the uridine phosphorylase was found to be abundant in sarcoma-180 solid tumor, leading to a significantly higher concentration of converted 5-fluorouracil in this tumor than in other normal tissues. This provides a good explanation for the high chemotherapeutic index of 5'-DFUR against this tumor, which may be applicable also for other tumors.

Antitumor effects of oral fluorinated pyrimidines including 5'-DFUR and their combination with recombinant interferon (rIFN) alpha A/D (Bgl) or cytostatics were investigated using various tumor models in mice. 5'-DFUR was more effective against Colon 26 than tegafur and 5-FU as a single agent, and their therapeutic indices were 14.7, 2.3 and 1.2, respectively. In combination with various cytostatics, 5'-DFUR as well as 5-FU and tegafur showed better efficacy against mouse Colon 26, Meth A fibrosarcoma and A755 adenocarcinoma than any other single agents. Combination therapy with 5'-DFUR and rIFN-alpha A/D also showed better efficacy against all seven murine tumors tested than their single therapy. In these combination therapies, increased toxicities measured by a body weight change and the incidence of toxic death were also observed to some extent. Among combinations with fluorinated pyrimidines, those with 5'-DFUR showed the toxicities at a lesser degree than those with 5-FU or tegafur. These results indicate that 5'-DFUR would be useful for the multiple combination chemotherapy like 5-FU and tegafur.

Antitumor activities of fluorinated pyrimidines by oral administration were compared with various murine tumor models. 5'-Deoxy-5-fluorouridine (5'-DFUR) showed a better antitumor activity in terms of the growth inhibition and increase of the survival time than those of 5-fluorouracil(FUra), tegafur and UFT, particularly with respect to the chemotherapeutic indices. The activity of these fluorinated pyrimidines were further investigated in more detail with mice bearing colon 26 adenocarcinoma to suggest some means to optimize their treatment regimens in clinical trials. 5'-DFUR showed the activity irrespective of the size of tumor mass at the time of start of therapy. Additionally only 5'-DFUR was safely administered to the mice daily for long period up to more than 100 days, suppressing the tumor growth and increasing the survival to great extent.

Studies of various analogs related to the antipicornavirus agent, 4',5-dihydroxy-3,3',7-trimethoxyflavone (Ro 09-0179), led to the identification of 4'-ethoxy-2'-hydroxy-4,6'-dimethoxychalcone (Ro 09-0410), a new and different type of antiviral agent. Ro 09-0410 had a high activity against rhinoviruses but no activity against other picornaviruses. Of 53 rhinovirus serotypes so far tested, 46 were susceptible to Ro 09-0410 in HeLa cell cultures. The concentration of Ro 09-0410 inhibiting 50% of the types of rhinovirus was about 0.03 micrograms/ml, whereas the 50% cytotoxic concentration was 30 microgram/ml. Ro 09-0410 inactivated rhinoviruses in direct dose-, time-, and temperature-dependent fashion. Since infectivity, reduced by exposure to the agent, completely regained the original level by extraction of the agent with chloroform, the inactivation may be associated with the binding of the agent to some specific site of the rhinovirus capsid.

The effect of thymosin alpha 1 was examined in mice immunosuppressed by cytostatics or X-ray irradiation. Inoculation of B16 melanoma or L1210 leukemic cells into these immunosuppressed mice caused a high incidence of pulmonary metastasis or rapid death, respectively. Thymosin alpha 1 given concomitantly with cytostatics or after X-ray prevented such deleterious effects of these agents. One of possible mechanisms causing the rapid death and increasing the metastasis is the damage to NK cells. Thymosin alpha 1 prevented the reduction of NK cell activity caused by these agents. The preventive activity could be transferred to immunosuppressed recipients by spleen cells and those deprived of T cells, but not by those deprived of NK cells. Another possible mechanism is the aberration of the barrier system for spread of tumor cells in blood circulation, which may allow the tumor cells to migrate to various sites in the host. In 5-FU-treated mice, distribution of 125I-L1210 cells upon inoculation was higher in blood and lung, but lower in liver and spleen as compared with that in normal mice. On the other hand, when thymosin alpha 1 was given with 5-FU, the pattern of the tissue distribution was almost the same as that in normal mice. Thus, thymosin alpha 1 protected mice which received immunosuppressive agents from undesirable effects of the agents on surveillance systems against tumor. Thymosin alpha 1 may be useful as an adjuvant in cancer therapies.

The immunosuppressive effect of 5'-deoxy-5-fluorouridine (5'-DFUR, Ro 21-9738) was examined for both humoral and cell-mediated immunity in mice in comparison with that of 5-fluorouracil and Ftorafur (FT-207). By both oral and intraperitoneal administration, 5'-DFUR was found to be much less suppressive than 5-fluorouracil and FT-207 in all immune responses tested; hemolysin plaque-forming cells, serum hemolysin titer, delayed-type hypersensitivity and allogeneic tumor rejection. Furthermore, 5'-DFUR did not induce any reduction in either the spleen weight, thymus weight, total spleen cell number, or peripheral leucocyte number.

The antitumor activity of indomethacin (IND) was investigated in mice bearing advanced colon 26 adenocarcinoma compared with its early transplants. Treatment with 0.001% IND in drinking water retarded the growth of tumor when commenced at Day 1 after the tumor inoculation. The suppression of the tumor growth by IND continued up to 4 to 5 weeks as long as the size of the tumor remained small. On the other hand, IND given to mice bearing a large burden of the tumor at 2 weeks after the inoculation had facilitated the tumor growth. IND reduced tumor-associated PGE2 production in mice bearing either small or large burdens of the tumors. These results indicate that the antitumor activity of IND depends on tumor size and therefore is not simply associated with the reduction of PGE2 levels. We found that colon 26 caused changes in parameters reported for tumor cachexia, such as weight loss, wasting of muscle and adipose tissues and hypoglycemia, when it grew to around 1 g at 2-3 weeks after the tumor inoculation. IND given to the mice with large burdens of colon 26 alleviated the cachexia of the mice, resulting in the increase of the survival time even though the growth of the tumor had been facilitated. It is possible that IND affects the tumor growth and survival by reversing tumor-induced disorders in homeostasis.

Enzyme levels of pyrimidine nucleoside phosphorylase, which is an essential enzyme for the phosphorolysis of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU), in normal and tumor tissues were investigated. In all mouse strains tested, the enzyme level was found to be higher in the small intestine and stomach than other tissues, while in rats a higher level of the enzyme in the lung was also observed additionally. The enzyme levels of tumor tissues varied in tumor cell lines transplanted. P388 leukemia, Ehrlich ascites carcinoma, sarcoma 180, colon 26 carcinoma, and Lewis lung carcinoma cells contained high levels of the enzyme and the mice bearing these tumors responded well to the therapy with 5'-DFUR than its active metabolite 5-FU, while 5'-DFUR did not show clear advantage over 5-FU against L1210 or LSTRA leukemia, in which the enzyme levels were low. These results indicate that there is some correlation between the enzyme level and antitumor efficacy of 5'-DFUR. In human specimens, the enzyme levels were 2-6 times higher in tumors than those of the corresponding normal tissues and those adjacent to the tumors. These results predict that 5'-DFUR seemed to be converted efficiently to 5-FU also in human tumors.

5'-Deoxy-5-fluorouridine (5'-DFUR) exhibits antitumor activity through its conversion to 5-fluorouracil by uridine phosphorylase (UPase) in mice. This mode of activation was confirmed by the fact that a mutant strain of Micrococcus flavus resistant to 5'-DFUR but sensitive to 5-fluorouracil was isolated and found to be deficient in UPase activity. Furthermore, since the enzyme level in tumor tissue should be useful as an indicator for therapy with 5'-DFUR, a simple assay method for the enzyme activity with use of the above bacterium was developed, in which the amount of 5-fluorouracil cleaved from 5'-DFUR by the enzyme was estimated through its antibacterial activity without separation from 5'-DFUR. This method is simple and efficient for handling a large number of samples.