Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolitebisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro-computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases.

The metastasis of tumor cells to bone can lead to osteolytic and osteosclerotic lesions, which cause severe, highly-localized bone destruction and abnormal bone apposition, respectively. Accurate quantification of lesion progression is critical to understand underlying mechanisms and assess treatment efficacy; however, standard structural parameters may be insensitive to local changes. We developed methods to quantify osteolytic and osteosclerotic lesions using micro-computed tomography (μCT) within in vivo mouse datasets. Two Balb/c nude datasets were used: (i) bone-homing MDA-MB-231 (osteolytic) cells injected into the left ventricle, treatment with alendronate or vehicle, and weekly μCT (proximal tibia) for 4 weeks, and (ii) MCF7 (osteosclerotic) cells injected into the right tibia and weekly μCT over 12 weeks. After registering images to baseline, osteolytic lesion volume was determined by summing all baseline bone voxels at distances greater than a threshold (150 μm) from the nearest follow-up. Osteosclerotic lesions were determined by measuring the distance from each follow-up surface voxel to the nearest baseline surface and calculating the standard deviation of distance values (SDDT) of the surrounding voxels. Bone mineral density (BMD), bone volume density (BV/TV), and separation (Sp) were determined for comparison. Osteolytic lesions were observed 1 week after tumor cell injection; however, no corresponding BV/TV losses or Sp increases were observed, indicating that standard parameters were unable to detect early metastatic changes. Lesion volume was smaller in the alendronate versus control group (15.0%, p = 0.004 and 18.6%, p = 0.002 of control lesion volume at weeks 3 and 4, respectively). In the osteosclerotic dataset, increased SDDT was observed following injection, providing a potential new measure of osteosclerotic bone apposition. These data show that quantification of local structural change with serial μCT may overcome the limitations of standard mineral and microstructural parameters, and successfully separates metastatic and normal bone turnover. © 2017 American Society for Bone and Mineral Research.

ZusammenfassungWir berichten über den äußerst seltenen Fall einer symptomatischen testikulären Metastasierung durch ein azinäres Adenokarzinom der Prostata. Bislang wurden Hodenmetastasen von Prostatakarzinomen (PCa) meist nur zufällig im Rahmen von therapeutischen Orchiektomien oder Autopsien entdeckt. Insgesamt wurden in der Literatur nur wenige klinische und v. a. symptomatische Fälle beschrieben. Trotz des raren Auftretens von Hodenmetastasen sollte bei fortgeschrittenen PCa differentialdiagnostisch an die Möglichkeit einer solchen Metastasierung gedacht werden.

No abstract

Patients with breast cancer bone metastases suffer significant morbity from skeletal-related events but an effective agent that inhibits bone resorption while maintaining bone formation has not been identified. In this study we tested the therapeutic efficacy of a novel drug, 5-FdU-ale, a conjugate between the anti-metabolite 5-FdU and the bisphosphonate alendronate, in a mouse model of breast cancer bone metastases. Administration of 5-FdU-ale in vitro induces cell cycle arrest similar to treatment with unconjugated 5-FdU. In vivo, mice harboring bone lesions treated with 5-FdU-ale showed a reduction in tumor size not observed with administration of either Alendronate or 5-FdU. Since osteolysis mediated release of growth factors from bone contribute to tumor growth, we show 5-FdU-ale treatment significantly reduces bone resorption, although uniquely, the inhibition of osteoclast activity is not mediated through inhibition of prenylation of small GTPases. Furthermore, and in contrast to Alendronate, there is no concomitant decrease in bone formation activity, as determined by serum osteocaclin levels. This finding is supported by micro-CT analyses which reveal significantly higher bone volume and histologically, pockets of tumor cells are observed largely confined to regions of marrow space between endochondral and trabecular bone. Taken together, we conclude that 5-FdU-ale has potent anti-tumor efficacy in osteolytic bone lesions mediated uniquely through bone formation activity of osteoblasts and inhibition of bone resorption. The study identifies the important role of osteoblast in not only preventing the osteolytic metastatic phenotype but as a means of harnessing the therapeutic potential of bone formation to treat osteolytic lesions. Citation Format: Christian Schem, Rob J Tower, Philipp Kneissl, Anna C Rambow, Graeme M Campbell, Thorsten Heilmann, Anna Trauzold, Walter Jonat, Claus C Glüer, Sarah Schott, Sanjay Tiwari. Inhibition of osteolytic tumor growth by 5-FdU-alendronate, a bisphosphonate conjugate that maintains bone formation: Implications for treatment of osteolytic bone lesions [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-17-02.

Summary Background The suitability of laparoscopic varicocelectomy for assisted reproductive technology depends on the improvement of semen parameters. The present study analyzed the improvement of semen parameters following laparoscopic varicocele ligation. Material and methods A retrospective study of the laparoscopic varicocele clippings at the Department of Urology of University Hospital of Kiel between the years 2007 and 2019 was conducted. The semen analyses according to WHO standards (sperm count, density, motility and morphology) were conducted before and 12 months after surgery. Screening for surgical complications took place at the time of the follow-up seminal analysis. Included were patients with oligozoospermia, asthenozoospermia and/or teratozoospermia (group 1, OAT) or with nonobstructive azoospermia (group 2, NOA). Results This study included data of 27 patients and 22 patients presented preoperative OAT (81%, group 1). Another 5 patients showed NOA (19%, group 2). Data of group 1 showed that semen parameters normalized in 32% of the patients after surgery. Significant improvement in total sperm count (p < 0.005), sperm density (p < 0.005) and total motile sperm count (p < 0.005) was observed. No deterioration of semen parameters was observed. In group 2 we detected spermatozoa in 1 case in the postoperative ejaculate. None of the patients showed complications according to the Clavien-Dindo classification, postoperative hydrocele formation or recurrence of varicocele at the time of control spermiogram. Conclusion Laparoscopic varicocelectomy is a valid therapeutic approach to improve semen parameters for further assisted reproductive techniques. Spermatogenesis may be induced for patients with NOA. Normalization of semen parameters can be achieved for patients with OAT.

No abstract