Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose

Thymidine phosphorylase (TP) catalyzes the reversible conversion of thymidine to thymine, thereby generating 2-deoxy-D-ribose-1-phosphate, which upon dephosphorylation forms 2-deoxy-D-ribose (D-dRib), a degradation product of thymidine. We have previously shown that D-dRib promotes angiogenesis and chemotaxis of endothelial cells and also confers resistance to hypoxia-induced apoptosis in some cancer cell lines. 2-Deoxy-L-ribose (L-dRib), a stereoisomer of D-dRib, can inhibit D-dRib anti-apoptotic effects and suppressed the growth of KB cells overexpressing TP (KB/TP cells) transplanted into nude mice. In this study, we examined the ability of L-dRib to suppress metastasis of KB/TP cells using two different models of metastasis. The antimetastatic effect of L-dRib was first investigated in a liver-metastasis model in nude mice inoculated with KB/TP cells. Oral administration of L-dRib for 28 days at a dose of 20 mg/kg/day significantly reduced the number of metastatic nodules in the liver and suppressed angiogenesis and enhanced apoptosis in KB/TP metastatic nodules. Next, we compared the ability of L-dRib and tegafur alone or in combination to decrease the number of metastatic nodules in organs in the abdominal cavity in nude mice receiving s.c. of KB/TP cells into their backs. L-dRib (20 mg/kg/day) was significantly (P < 0.05) more efficient than tegafur (100 mg/kg/day) in decreasing the number of metastatic nodules in organs in the abdominal cavity. By in vitro invasion assay, L-dRib also reduced the number of invading KB/TP cells. L-dRib anti-invasive activity may be mediated by its ability to suppress the enhancing effect of TP and D-dRib on both mRNA and protein expression of vascular endothelial growth factor and interleukin-8 in cultured KB cells. These findings suggest that L-dRib may be useful in a clinical setting for the suppression of metastasis of tumor cells expressing TP.     

Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression

Centrosome amplification frequently occurs in human cancers and is a major cause of chromosome instability (CIN). In mouse cells, centrosome amplification can be readily induced by loss or mutational inactivation of p53. In human cells, however, silencing of endogenous p53 alone does not induce centrosome amplification or CIN, although high degrees of correlation between p53 mutation and CIN/centrosome amplification in human cancer can be detected, suggesting the presence of additional regulatory mechanism(s) in human cells that ensures the numeral integrity of centrosomes and genomic integrity. Cyclin E, a regulatory subunit for CDK2 that plays a key role in centrosome duplication, frequently is overexpressed in human cancers. We found that cyclin E overexpression, together with loss of p53, efficiently induces centrosome amplification and CIN in human bladder cancer cells but not by either cyclin E overexpression or loss of p53 alone. We extended these findings to bladder cancer specimens and found that centrosome amplification is strongly correlated with concomitant occurrence of cyclin E overexpression and p53 inactivation but not with either cyclin E overexpression or p53 inactivation alone. Because cyclin E expression is strictly controlled in human cells compared with mouse cells, our findings suggest that this stringent regulation of cyclin E expression plays an additional role underlying numeral homeostasis of centrosomes in human cells and that deregulation of cyclin E expression, together with inactivation of p53, results in centrosome amplification.     

Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth

We evaluated the significance of the host kallikrein-kinin system in tumor angiogenesis and tumor growth using two rodent models genetically deficient in a kallikrein-kinin system. Inoculation of Walker 256 carcinoma cells into the s.c. tissues of the back of normal Brown Norway Kitasato rats (BN-Ki rats) resulted in the rapid development of solid tumors with marked angiogenesis. By contrast, in kininogen-deficient Brown Norway Katholiek rats (BN-Ka rats), which cannot generate intrinsic bradykinin (BK), the weights of the tumors and the extent of angiogenesis were significantly less than those in BN-Ki rats. Daily administration of B(2) receptor antagonists significantly reduced angiogenesis and tumor weights in BN-Ki rats to levels similar to those in BN-Ka rats but did not do so in BN-Ka rats. Angiogenesis and tumor growth were significantly suppressed in B(2) receptor knockout mice bearing sarcoma 180 compared with their wild-type counterparts. Immunoreactive vascular endothelial growth factor (VEGF) was localized in Walker tumor stroma more extensively in BN-Ki rats than in BN-Ka rats, although immunoreactive B(2) receptor also was detected in the stroma to the same extent in both types of rats. Cultured stromal fibroblasts isolated from BN-Ki rats and BN-Ka rats produced VEGF in response to BK (10(-8)-10(-6) m), and this stimulatory effect of BK was abolished with a B(2) receptor antagonist, Hoe140 (10(-5) m). These results suggest that BK generated from kininogens supplied from the host may facilitate tumor-associated angiogenesis and tumor growth by stimulating stromal B(2) signaling to up-regulate VEGF production mainly in fibroblasts.     

Therapeutic effects of Anastrozole in patients with advanced and recurrent breast cancer

We reviewed therapeutic effects and harmful side effects in 33 patients with advanced or recurrent breast cancer who underwent treatment with Anastrozole 1 mg/day in our department. The patients ranged in age from 40 to 83 years old (median, 59). The Performance Status was 0-2, and there was 1 case of advanced breast cancer and 32 cases of recurrent breast cancer. The duration of disease was from 5 to 233 months (median, 50 months). The estrogen and/or progesterone receptor-positive rate was 72.7%. Metastatic sites were in multiple organs in 9 cases, in the lung only in 1 case, in bone only in 12 cases, and in soft tissue only in 10 cases. First-line therapy was used in 10 cases, second-line therapy in 6 cases, and above third-line therapy in 17 cases. There was a complete response in 3 cases, partial response in 5 cases, no long change in 13 cases, no change in 9 cases, and progressive disease in 3 cases. The response rate was 24.3%, The response period ranged from 2 to 22 months (median, 8 months), and clinical benefit was achieved in 63.7%. The clinical benefit rates for first-line were 60%, second-line 83.3% and above third-line therapy 58.8%. The response rate for patients with breast cancer resistant to Anthracyclines and/or Taxanes was 20%. Time-to-progression ranged from 2 to 28 months (median, 11 months), and overall survival ranged from 7 to 30 months (median, 15 months). The most frequent harmful side effects were rise in total cholesterol, general fatigue, hot flashes and arthralgia (9.1%). In this study, we confirmed the availability and safety of Anastrozole, which was suggested to be a useful drug in salvage therapy for patients having resistance to Anthracyclines and/or Taxanes, not only but also useful as a first- or second-line therapy.     

Acute myeloid leukemia presenting with obstructive jaundice and granulocytic sarcoma of the common bile duct

A 55-year-old man presented with jaundice and edema of the right leg. Tests of the peripheral blood and bone marrow showed leukocytopenia with 6% blasts and 38.3% of myeloperoxidase-positive blasts, respectively. Computed tomography (CT) scanning disclosed thickening of the common bile duct wall. Granulocytic sarcomas were also found at the left chest wall and the pelvic floor. Endoscopic retrograde cholangiopancreatography confirmed the narrowing of the common bile duct. Biopsy specimens of the common bile duct and pelvic masses revealed myeloblastic infiltration. After placement of a naso-biliary drainage tube, chemotherapy consisting of cytarabine (100 mg/m2/ day for 7 days) and idarubicin (12 mg/m2/ day for 3 days) was commenced. The dose of idarubicin was not modified. No serious complications, including delayed hematopoietic recovery, were observed after chemotherapy, and a complete remission was obtained 35 days later. Jaundice and liver dysfunction also gradually improved. The patient continues to receive consolidation therapy and remains in remission 8 months after the onset of his illness.