Chronic low-dose isotretinoin treatment limits renal damage in subtotally nephrectomized rats.

Retinoids are anti-proliferative and anti-inflammatory compounds. We had previously shown that retinoids alleviate kidney damage in acute models of renal disease. We now examined whether retinoids are also effective in a chronic renal ablation model. Subtotally nephrectomized rats (SNx; two-third ablation) were compared to sham-operated controls (sham). SNx rats were administered either 10 mg/kg b.w. (low dose, LD) or 40 mg/kg b.w. (high dose, HD) isotretinoin or vehicle (n = 10 per group). The experiment was terminated after 16 weeks. Systolic blood pressure was significantly higher after SNx compared to sham but lower in SNx with LD isotretinoin (vs. SNx + vehicle). Compared to SNx + vehicle, SNx + LD isotretinoin had lower glomerular cell numbers, less glomerular hypertrophy and sclerosis, and less interstitial expansion. Morphological improvement in SNx + LD isotretinoin was accompanied by improvement in creatinine clearance and reduced urinary albumin excretion. In contrast, HD isotretinoin caused aggravation of renal damage with fibrinoid necroses of vessels and elevated urinary albumin excretion despite lower blood pressure. The dichotomous effects of isotretinoin are at least in part due to time- and dose-dependent alterations of transforming growth factor beta1 and collagen IV gene expression as also suggested by cell-culture studies in vascular smooth muscle cells. In addition, isotretinoin affected the systemic and the renal renin-angiotensin system (which was further analyzed in a model of angiotensin II infusion of the rat). Isotretinoin failed to cumulate at LD but cumulated at HD in SNx. We conclude that LD isotretinoin attenuates progressive renal damage, whereas HD isotretinoin cumulates and aggravates renal damage independent of blood pressure reduction.

Focal progression in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: a three-center-based study of 38 patients.

BACKGROUND: This study aimed to investigate the outcome of patients with advanced gastrointestinal stromal tumors (GISTs) exhibiting focal disease progression during imatinib therapy, treated by surgical resection and imatinib continuation. METHODS: A consecutive series of 38 patients with metastatic GISTs who underwent treatment with imatinib at our centers during a defined period of time was evaluated. Patients were evaluated for demographics including tumor-related features, initial response, disease recurrence, and salvage treatment modalities, and were classified as having either focal or generalized progression upon presentation prior to salvage therapy. RESULTS: After a median follow-up of 31.8 months, 25 of the 38 (65.8%) patients had progressed. Nine (36%) patients were classified as having focal and 16 (64%) as having generalized progression. Salvage therapies were: surgical resection and imatinib dose escalation in patients exhibiting focal progression and imatinib dose escalation alone in the majority of patients exhibiting generalized progression. Focal progression was associated with prolonged progression-free survival (PFS) and overall survival (OS) after salvage therapy as compared with generalized progression (median PFS and OS, 11.3 months and not attained, versus 2.5 and 22.8 months, respectively). Six-month PFS was 89% and 39% in patients exhibiting focal and generalized progression, respectively. KIT mutation analysis of controlled and progressive lesions was performed in 4 patients with focal progression. Secondary KIT mutations affected progressive lesions, whereas nonprogressive lesions harbored the original mutations only. CONCLUSION: Patients with advanced GIST exhibiting focal disease progression during imatinib therapy may benefit from surgical resection and imatinib continuation. Imatinib resistance seems to be partial in these patients.

Mitomycin C, 5-fluorouracil, leucovorin, and oxaliplatin as a salvage therapy for patients with cisplatin-resistant advanced gastric cancer: a phase I dose escalation trial.

BACKGROUND: This study aimed at evaluating the feasibility and toxicity of a salvage therapy with mitomycin C (MMC), 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with cisplatin-resistant advanced gastric cancer. METHODS: A 3-patient cohort dose-escalating study design was used. The patients received FLO: oxaliplatin 85 mg/m2, 5-FU 2,600 mg/m2 (24 h), leucovorin 200 mg/m2 on days 1, 15, and 29 plus MMC on day 1 (FLOM). The MMC dose was escalated from 6 to 12 mg/m2 in 2- mg/m2 steps. Cycles were repeated every 6 weeks. RESULTS: Twenty patients were enrolled in 4 treatment cohorts. The treatment was well tolerated with grade 3 or 4 nonhematological toxicities affecting less than 5% of patients. Grade 3 or 4 neutropenia, anemia, and thrombocytopenia were observed in 9 (45%), 7 (35%), and 5 (25%) of 20 patients, respectively. Mild but prolonged thrombocytopenia was dose limiting, requiring treatment discontinuation or a treatment delay >or=2 weeks in 8 (40%) of 20 patients. MMC 10 mg/m2 every 6 weeks was considered as the optimal dose in combination with FLO. Objective responses were observed in 7 (35%) of 20 patients, and 7 further patients (35%) had stable disease. Median time to progression and overall survival were 4.1 and 8 months, respectively. CONCLUSIONS: Prolonged cumulative myelotoxicity was dose limiting in the therapy with MMC, 5-FU, and oxaliplatin. This combination chemotherapy seems to overcome cisplatin resistance in patients with advanced gastric cancer.

Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis.

Transforming growth factor-beta1 (TGF-beta 1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-beta system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n = 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8), i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-beta 1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P < 0.025). The increase of cortical TGF-beta 1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P < 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P < 0.05). In all-trans retinoic acid-treated animals with Thy-GN, the increase of glomerular TGF-beta 1 protein (P < 0.008) and TGF-beta 1 (P < 0.025) and TGF receptor II mRNA (P < 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-beta 1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-beta 1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P < 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-beta 1 and TGF receptor II expression.

Retinoic acid reduces glomerular injury in a rat model of glomerular damage.

ABSTRACT.: In the reaction of kidneys to injury, cytokine-driven proliferation plays an important role and precedes the development of glomerulosclerosis. There is great interest in agents that may interfere with such proliferation. Therefore, a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy1.1) was studied, and the effects of all-trans-retinoic acid (all-trans-RA) and isotretinoin, powerful antiproliferative and anti-inflammatory substances, on glomerular damage and cell proliferation were examined. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans-RA or 40 mg/kg body wt isotretinoin (n = 9 to 11 per group), using either a pretreatment (days -2 through 8) or posttreatment (days +3 through +8) protocol, i.e., starting before or after the induction of anti-Thy1.1 nephritis, respectively. All-trans-RA prevented the BP increase evoked by anti-Thy1.1 (anti-Thy1.1/vehicle, 112.2 +/- 4.8 mmHg; anti-Thy1.1/RA, 87.5 +/- 2. 5 mmHg; P < 0.001). Treatment with all-trans-RA or isotretinoin produced a 70% decrease in the urinary albumin excretion rate (P < 0. 02). Periodic acid-Schiff staining of saline-perfused kidneys (day 8) revealed significantly fewer glomerular cells in RA-treated nephritic rats (anti-Thy1.1/vehicle, 97 +/- 3.1 cells/glomerulus; anti-Thy1.1/RA, 80 +/- 4.4; P < 0.02; control/vehicle, 69 +/- 1.2). No difference was observed between all-trans-RA and isotretinoin treatment. The capillary occlusion scores were significantly lower for the anti-Thy1.1/RA-treated group (1.9 +/- 0.1) than for the anti-Thy1.1/vehicle-treated group (2.9 +/- 0.5, P < 0.001). In the anti-Thy1.1/vehicle-treated group, 11.9 +/- 1.1 glomerular cells were proliferating cell nuclear antigen-positive; however, in the anti-Thy1.1/RA-treated group, only 5.3 +/- 0.8 cells were proliferating cell nuclear antigen-positive (P < 0.002; control, 2.2 +/- 0.2). Glomerular mitoses were reduced by 67% in the anti-Thy1. 1/RA-treated group, compared with the anti-Thy1.1/control group (P < 0.002). Glomerular staining for platelet-derived growth factor B-chain was significantly reduced in anti-Thy1.1-treated nephritic rats in the presence of isotretinoin or all-trans-RA, compared with the vehicle-treated group (P < 0.001). It is concluded that all-trans-RA limits glomerular proliferation, glomerular lesions, and albuminuria in an established model of renal damage. The findings point to retinoids as potential novel modulators of glomerular injury.