Direct intra-tumour delivery of zoledronate is superior to systemic administration for mitigating metastasis- induced bone destruction
Bibliographic record
Abstract
Background: Bone metastases are the most common cause of cancer-related pain and often lead to other complications. Bisphosphonates (BPs) are a class of potent anti-resorptive agents have been found recently to have direct anti-tumour properties. Currently, the use of BPs for cancer therapy is generally restricted to high dose systemic delivery. Questions/ purpose: (1) whether local delivery of BPs can inhibit tumour-induced osteolysis and tumour growth in an animal model of bone metastases; and (2) whether the efficacy in impairing cancer-induced osteolysis that is achieved by local delivery of BPs is comparable to that of systemic BPs treatment. Methods: Seven days following intra-tibial inoculation of MDA-MB-231 human breast cancer cells (N = 105) in athymic nude mice, the experimental group (N = 11) was treated by local administration of 2µg of zoledronate into the tibial lesion (three times/week for three weeks) and compared to vehicle-treated mice (N = 5). The formation of bone metastases and growth of the lesions were followed up by weekly bioluminescence imaging. In a subsequent experiment, a comparison of the effects of local versus systemic delivery of zoledronate on the formation of osteolytic bone metastases was carried in athymic mice (N = 19). The systemic group (N = 5) was treated with zoledronate (0.025mg/kg) once per week for 4 weeks and compared to systemic delivery of vehicle (N = 4). The local group (N=6) was treated by direct infusion of zoledronate (0.025mg/kg) once per week for 4 weeks and compared to local delivery of vehicle (N = 4). The effect of treatment on bone was determined using micro-computed tomography (μ-CT), and on tumour cells proliferation and apoptosis by immunohistochemistry using antibodies for Ki-67 and caspase-3. Results: The first experiment showed a statistically significant increase in mean bone volume/tissue volume % (BV/TV) in the treated group (12.30±2.80%) as compared to the control group (7.13±1.22%) (P<0.001, 95%CI=3.10-7.30). This corresponded to a net increase of 72.51% in response to zoledronate treatment. Bioluminescence imaging showed insignificant inhibition of the tumour growth in the treated group. Additionally, the treated group had an insignificant decrease in Ki-67-positive cells and this was mirrored with an insignificant increase in the number of caspase-3-positive cells. Comparison between the local and systemic effects of zoledronate also revealed a significant increase in the BV/TV in the locally treated group (10.90±1.25%) when compared to the cohort administered systemic bisphosphonate treatment (7.53±0.75%) (P<0.001, 95%CI=2.10-4.81), corresponding to a net increase of 44.8%. Conclusion: These preliminary results suggest that high dose sustained release of BPs can lead to a significant inhibition of tumour-induced osteolysis. Moreover, comparison between local and systemic delivery revealed that the effect of local BPs administration exceeds the benefits of systemic delivery in terms of osteolysis inhibition. Lastly, the noted effect of BPs local delivery triggers the need for further assessment of its anti-tumour activity.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".