Growth arrest by sulfasalazine (SASP) of subrenal capsule prostate cancer xenografts in immuno-deficient mice is coupled to a decrease in the number of tumor-associated macrophages
Bibliographic record
Abstract
5865 SASP is an established anti-inflammatory drug which at low levels (0.2 mM) specifically inhibits cellular cystine uptake mediated by the xc- plasma membrane cystine transporter. As such, SASP can be used to arrest proliferation of cancer cells which critically depend for growth on extracellular cystine (or cysteine, the reduced form). We have previously shown that SASP can arrest growth of lymphoma cells via cyst(e)ine starvation by inhibiting (i) their uptake of cystine via the xc- transporter and (ii) secretion of cysteine, an xc--mediated process, by fibroblasts in their environment acting as cysteine suppliers. Notably, intraperitoneal administration of SASP to rats markedly inhibited growth of lymphoma transplants (Anti-Cancer Drugs 14:21, 2003). Further studies aimed at prostate cancer showed that DU-145 and PC3 human prostate cancer cells have a critical requirement for extracellular cystine, in contrast to LNCaP cells capable of synthesizing cysteine. As expected, LNCaP cells were much less sensitive in vitro to SASP-induced growth arrest than DU-145 and PC3 cells. In the present study, the response of LNCaP xenografts in immuno-deficient mice to treatment with SASP was compared with that of DU-145 and PC3 tumors. Groups of male, testosterone-supplemented Rag-2M mice were used, carrying established LNCaP cell xenografts (about 80 mm3) under the kidney capsules. Every 12 h they received i.p. injections of saline (controls; n=4) or SASP (250 mg/kg body wt; n=7) for 8 days. Animals were then sacrificed and tumors harvested for volume measurement and histological analysis (H&E and macrophage staining, using biotinylated, rat antimouse macrophage antibodies). It was found that LNCaP xenografts were surprisingly sensitive to SASP treatment, showing growth arrests of about 70% (relative to controls), comparable to growth arrests found for DU-145 and PC3 tumors. Immunohistochemical analysis revealed presence in control mice of numerous mouse macrophages lining tumor-kidney boundaries. In contrast, the numbers of such tumor-associated macrophages (TAMs) were markedly reduced in SASP-treated mice. Administration of SASP (i.p.) has been reported to decrease numbers of mouse macrophages. Taken together, the results suggest that the growth arrest of LNCaP tumors by SASP may be due to a reduction in the number of TAMs and consequently their tumor growth-promoting activity, recently recognized as an important factor in cancer development. In the case of DU-145 and PC3 tumors, a reduction in immunologically activated TAMs would likely also lead to decreased cysteine supply. SASP, an old drug, may be useful in prostate cancer therapy for targeting tumor growth-promoting macrophages. Supported by CIHR and DOD US Army.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 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) | 0.003 | 0.001 |
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".