Mode of antitumor action of recombinant human tumor necrosis factor on the sarcoma Meth A transplanted in the mouse

The mode of antitumor action of rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation with respect to time course, dose-response relationships and selectivity of the effects. The maximal cytotoxic effect on tumor cells revealed by inhibition of DNA synthesis and maximal lesional effect on tumor vasculature revealed by change in blood pool-size in the tissue were detected at 30 min and I h after administration of rHu-TNF, respectively. The dose-response relationship between cytotoxic and tumoricidal effects of rHu-TNF was irrespective of administration route. ED₅₀s of these antitumor effects afteri.v. administration of rHu-TNF were about 50 times as high as ED₅₀s afteri.t. administration. ED₅₀ ofi.t. given rHu-TNF for vascular effect was about 20 times as high as that for cytotoxicity while ED₅₀ ofi.v. rHu-TNF for vascular effect was only 2–3 times as high as that for cytotoxicity. The whole body autoradiographies with [¹²⁵I] HSA giveni.v. to see the blood influx into tumor tissue and [¹⁴C]thymidine given i.v. to see DNA synthesis in the whole body after administration of rHu-TNF revealed that the distribution of radioactivity was markedly changed in the tumor alone without any detectable change in other whole body tissues.In conclusion, thein vivo antitumor effect of rHu-TNF giveni.t. ori.v., appears to be exerted through the direct action on Meth A sarcoma rather than indirectly on tumor vasculature. Under present conditions, the effect of rHu-TNF in the whole body tissues seems rather selective on cells and vasculature of the tumor.     

Nematodes of the family Heligmonellidae (Trichostrongyloidea) collected from rodents of the Ryukyu archipelago and Taiwan

Six species of the family Heligmonellidae (Nematoda: Trichostrongyloidea), including 3 new species, are recorded from rodents of the subfamily Murinae in the Ryukyu Archipelago and Taiwan. Heligmonoides ikeharai n. sp. from Tokudaia osimensis muenninki on Mt. Yonaha, Okinawa Island, is characterized by extremely long spicules and hypertrophied ridges in the prevulval region. Heligmonoides taiwanensis n. sp. from Apodemus draco on Mt. Alishan, Taiwan, is distinguished from other members of the genus in having a markedly asymmetrical bursa and stout bursal rays. Heligmonoides alishanensis n. sp. from Niviventer confucianus on Mt. Alishan differs from the allied forms in lacking hypertrophied ridges at the level of the middle of the spicules and in having longer spicules and a smaller body. Nippostrongylus sp. from N. confucianus on Mt. Alishan resembles Nippostrongylus brasiliensis but is distinguishable in that the externolateral ray is almost the same length as the lateroventral ray in the left lobe, and the fused tips of the spicules are thin and straight. Heligmonoides ryukyensis from Mus caroli and Orientostrongylus tenorai from Bandicota indica are first recorded from Taiwan. Heligmonellid nematodes parasitic in wild rodents in these areas are considered to have been introduced with their hosts from the mainlands of China and Japan through land connections in the Pleistocene.     

Close linkage of MEN2A with RBP3 locus in Japanese kindreds

Summary The gene responsible for multiple endocrine neoplasia type 2A (MEN2A) has recently been assigned to the pericentromeric region of chromsome 10 in European Caucasian kindreds by linkage analysis using a DNA marker, interstitial retinol-binding protein 3 (RBP3). We have found tight linkage between the MEN2A and RBP3 loci in Japanese MEN2A kindreds. The maximum lod score is 5.19 at a recombination fraction of 0.00. This result suggests that mutation of a certain gene close to RBP3 is responsible for MEN2A irrespective of ethnic backgrounds.     

Intravesical treatment of bladder cancer with recombinant human interferon-β

Summary In order to examine its clinical efficacy, recombinant human interferon- (rIFN-) was instilled intravesically into 51 patients with superficial bladder cancer. Ten patients, who received intermittent intravesical instillation at a dose of (3–36) × 10⁶ U rIFN- on days 1–3 every week, showed no response. Thirty-two patients received intravesical instillation at a dose of (3–36) × 10⁶ U every day for 10–20 days. Eight patients showed partial response, indicating an efficacy rate of 25%. Nine patients received divided doses of 18 × 10⁶ U twice a day every day for 10–20 days. Six patients showed partial response, indicating an efficacy rate of 67%. This value was significantly higher than that obtained by administering divided doses. The response to intravesical instillation therapy with rIFN- varies with treatment protocol. Frequent and longer exposure to rIFN- may induce better regression of superficial bladder cancer. Six incidences of side-effects were found in five cases (9.8%): pollakiuria in one, pain on micturition in two, fever in two, and eruption in one case. All of these side-effects were slight and reversible after drug withdrawal. Laboratory tests showed only a few changes with low severity. Thus, rIFN- is potentially a new drug for instillation therapy of superficial bladder cancer, in view of the absence of adverse effects.     

Antimetastatic effect of endogenous tumor necrosis factor induced by the treatment of recombinant interferon γ followed by an analogue (GLA-60) to synthetic lipid A subunit

Summary We have investigated the effect of endogenous production of tumor necrosis factor (TNF) induced by the combination of recombinant interferon (rIFN) as a primer followed by GLA-60 as a trigger (rIFN/GLA-60) on murine lung metastases caused by B16-BL6 melanoma. In order to examine the therapeutic effect of endogenous TNF on tumor metastasis, the ability of multiple administrations of rIFN/GLA-60 to induce TNF production was also tested. The multiple administrations of rIFN/GLA-60 at intervals of 2 days were effective for the induction of endogenous TNF in mice but continuous multiple administrations of them for 2–4 days were not. In tumor-bearing mice, the production of endogenous TNF by rIFN/GLA-60 was less than that of normal mice, but treatment 3 days after the surgical excision of primary tumors showed the endogenous TNF production to be similar to that in normal mice. In the experimental lung metastasis model, intravenous administration of rIFN followed by intravenous or intranasal administration of GLA-60 showed potent inhibition of lung metastases of B16-BL6 melanoma, whereas the reverse sequence of administration (GLA-60/rIFN) or administration of a mixture of rIFN and GLA-60, which cannot induce the production of TNF, caused no inhibition of lung metastases. These results indicated that the regression of tumor metastases by rIFN/GLA-60 was mediated by the production of endogenous TNF in addition to the direct effects of both immunostimulants. Furthermore, the administration of rIFN and GLA-60 significantly inhibited the tumor metastases in spontaneous lung metastasis model. These results may provide a promising approach for the treatment of cancer metastasis as a result of its ability to induce endogenous TNF.     

Carbon Use Efficiency and Cell Expansion of NaCl-Adapted Tobacco Cells

Carbon use efficiencies (gram cell organic dry weight accumulated per gram sugar assimilated from the medium) of unadapted and NaCl-adapted (428 millimolar) cells of tobacco (Nicotiana tabacum L. var Wisconsin 38) were determined to evaluate metabolic costs associated with growth and survival in a saline environment. No net increase in carbon costs was associated with salt adaptation. At low substrate levels, carbon use efficiencies of unadapted and NaCl-adapted cells were not appreciably different (0.495 and 0.422, respectively) and at higher substrate levels carbon use efficiency of NaCl-adapted cells was clearly higher than that of unadapted cells. These results indicate that a homeostasis of metabolic efficiency is established after cells have adapted to NaCl. Altered carbon availability does not cause the reduced cell volume that results from adaptation to NaCl. This does not preclude, however, the possibility that altered intracellular partitioning of carbon affects cell expansion.     

Copulatory behavior unaccompanied by ovulation in the Japanese monkey (Macaca fuscata)

Copulatory behavior unrelated to conception is sometimes observed in some non-human primates including the Japanese monkey. In the present study, the authors examined whether a mature follicle or a newly formed fresh corpus luteum was observed in the ovaries of female Japanese monkeys which displayed the copulatory behavior unrelated to conception. Post-conception copulatory behaviors were observed in three out of four females usually kept in individual cages in an air-conditioned room, and in two out of three females without infants kept in an outdoor group cage. However, neither a mature Graafian follicle nor a fresh corpus luteum formed newly after conception was observed in any of these females by laparoscopic examinations conducted immediately after termination of the copulatory behavior. In females with infants born in the preceding birth season, copulatory behaviors were observed in three out of four females kept in the outdoor group cage, and in two out of four females in a free-ranging troop. Ovulation was confirmed in one case out of the three kept in the outdoor group cage, but neither a mature follicle nor a newly formed corpus luteum was observed in the remaining four females. These findings suggest that copulatory behavior in the Japanese monkey is not always controlled by the development of a follicle or ovulation in the ovary.     

Two new nematodes from the Iriomote cat, Prionailurus iriomotensis, from Okinawa: Uncinaria (Uncinaria) maya n. sp. (Ancylostomatoidea) and Molineus springsmithi yayeyamanus n. subsp. (Trichostrongyloidea)

Uncinaria (Uncinaria) maya n. sp. (Nematoda: Ancylostomatidae) and Molineus springsmithi yayeyamanus n. subsp. (Nematoda: Molineidae) are described from the Iriomote cat, Prionailurus iriomotensis, on Iriomote Island, Okinawa, Japan. Uncinaria (U.) maya resembles Uncinaria (Uncinaria) felidis Maplestone, 1939, from Prionailurus bengalensis of India but is distinguished in that the body is much smaller, the ventral rays are set closely with the lateral rays, and the externolateral ray is much shorter than other laterals. Molineus springsmithi yayeyamanus differs from Molineus springsmithi springsmithi Inglis and Ogden, 1965, from Prionailurus bengalensis horsfieldi of East Nepal in that the body is much longer, whereas the esophagus is somewhat shorter and the spicules are divided more distally. Presence of the closely related nematodes in both the Iriomote cat and P. bengalensis suggests a close evolutionary relationship of the 2 hosts.