Treatment Of Advanced Renal Carcinoma Research Articles

Therapeutic effects and underlying mechanism of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol)/combretastatin A4/BLZ945 nanoparticles on Renca renal carcinoma.

Introduction: The prognosis of advanced renal carcinoma is not ideal, necessitating the exploration of novel treatment strategies. Poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)/Combretastatin A4 (CA4)/BLZ945 nanoparticles (CB-NPs) possess the dual capability of CA4 (targeting blood vessels to induce tumor necrosis) and BLZ945 (inducing M2 macrophage apoptosis), thereby inhibiting tumor growth. Methods: Here, the therapeutic effects and underlying mechanism was explored by CCK-8 cytotoxicity experiment, transwell cell invasion and migration experiment, H&E, western blot analysis, immunohistochemistry, flow cytometry, and other techniques. Results: These results demonstrated that CB-NPs could inhibit the growth of Renca cells and subcutaneous tumors in mice, with an impressive tumor inhibition rate of 88.0%. Results suggested that CB-NPs can induce necrosis in renal carcinoma cells and tissues, downregulate VEGFA expression, promote renal carcinoma cell apoptosis, and reduce the polarization of M2 macrophages. Discussion: These findings offer innovative perspectives for the treatment of advanced renal carcinoma.

The Diagnostic Value of Serum Ang, VEGF, and CRP Combined with the Chinese Medicine Antitumor Formula in the Treatment of Advanced Renal Carcinoma.

Objective To explore the diagnostic value of serum angiopoietin (Ang), vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) combined with the Chinese medicine antitumor formula in the treatment of advanced renal carcinoma. Methods Retrospective analysis was performed for the data of 60 patients with advanced renal cancer admitted at Yantaishan Hospital from February 2019 to February 2020. All patients were treated with Chinese medicine antitumor formula. The serum Ang, VEGF, and CRP levels in venous blood samples were detected before and after treatment. Sensitivity, specificity, and AUC of combined serum Ang, VEGF, and CRP were analyzed utilizing the receiver operating characteristic curve (ROC) (95% CI). Results There were 52 cases of clear-cell carcinoma (86.7%), 7 cases of papillary carcinoma (11.7%), and 1 case of chromophobe renal cell carcinoma (1.7%). The average tumor diameter was (9.67 ± 0.65) cm, and the KPS score was (74.68 ± 1.52). About 75% of the patients had metastasis. After treatment, the level of serum Ang, VEGF, and CRP was immensely lower compared to that before treatment (P < 0.001). The sensitivity, specificity, and AUC (95%CI) of the combined detection of Ang, VEGF, and CRP before treatment were 86.7%, 90.0%, and 0.883 (0.817–0.950), while the sensitivity, specificity, and AUC (95%CI) of the combined detection of Ang, VEGF, and CRP were 83.3%, 86.7%, and 0.850 (0.776–0.9524), respectively. Conclusion The combined detection of serum Ang, VEGF, and CRP has high diagnostic value for patients with advanced renal cancer treated with Chinese medicine antitumor formula.

The induction of AMPK-dependent autophagy leads to P53 degradation and affects cell growth and migration in kidney cancer cells

The most common subtype of renal cell carcinoma (RCC) is the clear cell RCC (ccRCC) that accounts for 70–80% of cases. The fate of ccRCC is linked to alterations of genes that regulate TP53. The dysfunction of p53 affects several processes including autophagy, which is increased in different advanced carcinomas and could be associated with cancer progression.We report that different kidney cancer cell lines show higher levels of autophagy than control cells. The increased autophagy is associated with the upregulation of miR501-5p, which stimulates mTOR-independent autophagy by the activation of AMP kinase. AMPK activation occurs through the decrease of ATP generation caused by the downregulation of the mitochondrial calcium uniporter (MCU) that leads to the reduction of mitochondrial calcium uptake. Autophagy induction promotes the degradation of p53 through the autophagolysosomal machinery. Consistently, the inhibition of autophagy reduces both cell proliferation and migration enhancing the expression of p53, p21 and E-Cadherin as well as decreasing Vimentin synthesis. Taken together, these findings indicate that autophagy is involved in the progression of kidney cancer. Therefore, the pharmacological targeting of this process could be considered an interesting option for the treatment of advanced renal carcinoma.

Sorafenib and everolimus (RAD001) in the treatment of patients with advanced clear cell renal carcinoma (RCC): A Sarah Cannon Research Institute phase I/II trial.

4629 Background: Sorafenib and everolimus are standard agents with different targets (VEGFR and m-TOR, respectively) for the treatment of advanced RCC. Combined use of these agents may improve efficacy. This phase I/II trial established the maximum tolerated dose (MTD) for these agents when used in combination, and then evaluated this combination in advanced RCC. Methods: Eligible patients had metastatic or unresectable recurrent clear cell RCC, and had received 0 or 1 previous regimen for advanced RCC. Additional entry criteria: ECOG PS 0–1, prior nephrectomy (unless medically inappropriate), no active CNS metastasis, adequate liver/kidney/marrow function, informed consent. Sorafenib was given PO daily; everolimus PO once weekly. Patients were evaluated for response every 8 weeks; treatment continued until progression. Results: 10 patients entered the phase I portion; the MTDs were sorafenib 400mg PO qd and everolimus 35mg PO weekly (DLTs: rash, hand-foot syndrome). 50 patients enrolled in the phase II p...

Direct in vivo evaluation of tumor VEGFR in response to treatment with pazopanib: A novel molecular imaging study.

3049 Background: Several small molecule tyrosine kinase inhibitors (TKI) targeting VEGFR are already approved for use in anti- angiogenic therapy either alone or in combination with chemotherapeutics. Unfortunately, the clinical response to such therapy varies markedly among individuals. We hypothesize that noninvasive assessment of changes in VEGFR prevalence in response to TKI treatment would identify responsive patients. We report here that SPECT(single photon emission computed tomography) imaging of VEGFR-2 in HT29 tumor xenografts allows for detailed assessment of its prevalence in the course of treatment with pazopanib, a TKI targeting VEGFR, PDGFR and c-Kit, recently approved for the treatment of advanced renal carcinoma. Methods: VEGFR-2 SPECT imaging was done using scVEGF/Tc, an engineered single chain (sc) form of VEGF radiolabeled with 99mTc. This tracer binds to and is internalized by VEGFR-2 in tumor vasculature, allowing for selective accumulation of 99mTc in tumor endothelial cells. All SPECT imaging experiments were carried out on HT29 tumor xenografts on Swiss nude mice. A dose of 2-4 mCi of [99mTc]scVEGF was injected into the retro-orbital venous sinus in a volume of 100 to 220 μ L followed by imaging two hours later. Quantitative histogram analysis of the SPECT images was performed. At the end of imaging experiments the mice were sacrificed and the tumors were harvested for immunohistochemical analysis (IHC) of VEGFR-2 and VEGFR-1, as well as panendothelial marker CD31. Results: The imaging results, which are consistent with IHC analysis, show that VEGFR-2 levels in tumors were significantly reduced upon treatment with pazopanib as early as day 5 after the initiation of therapy, when morphological changes were barely detectable. A detailed kinetic study to understand the dose dependence of the effects of pazopanib on tumor VEGFR is in progress and those results will also be presented. Conclusions: This is the first direct evaluation of tumor VEGFR in response to a VEGFR targeted therapy. In principle, this technology can be extended to human use providing for new opportunities in treatment management of VEGFR-targeted therapies including patient selection, dose, and optimal drug regimen. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Sib Tech Inc GlaxoSmithKline, Sib Tech Inc GlaxoSmithKline

Cytotoxic and Anticancer Activities of Isatin and Its Derivatives: A Comprehensive Review from 2000-2008

Isatin (1H-indole-2,3-dione) and its derivatives demonstrate a diverse array of biological and pharmacological activities including anticonvulsant, antibacterial, antifungal, antiviral and anticancer properties. This broad spectrum of biochemical targets has been facilitated by the synthetic versatility of isatin, which has allowed the generation of a large number of structurally diverse derivatives including analogues derived from substitution of the aryl ring, and/or derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. The recent FDA approval of the oxindole sunitinib malate, as a kinase inhibitor for the treatment of advanced renal carcinoma and gastrointestinal stromal tumours, underscores the increasing interest in isatins as a new class of antineoplastic agents. In addition to potent kinase inhibition, the mechanism of action of other isatin derivatives includes the inhibition and/or modulation of proteases, translation initiation, neo-vascularisation and tubulin polymerisation. It was therefore the objective of this review to systematically evaluate the cytotoxic and anticancer properties of various substituted isatins and collate these findings to be used as a guide for future structure-activity relationship and mode of action studies. This is the first review to comprehensively discuss the in vitro and in vivo anticancer activities of isatin and its substituted derivatives.

Sorafenib With Interferon Alfa-2b As First-Line Treatment of Advanced Renal Carcinoma: A Phase II Study of the Southwest Oncology Group

This phase II study evaluated the activity of combined treatment with interferon alfa-2b and sorafenib, a Raf and multiple receptor tyrosine kinase inhibitor, in patients with advanced renal carcinoma. Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. Treatment consisted of interferon alfa-2b 10 x 10(6) U subcutaneously three times weekly and sorafenib 400 mg orally bid. The primary end point was confirmed Response Evaluation Criteria in Solid Tumors response rate. Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4 to 11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminase elevation. Von Hippel-Lindau gene mutations were detected in four (22%) of 18 archival tumor specimens. The confirmed response rate for the combination of sorafenib and interferon in advanced renal carcinoma is greater than expected with either interferon or sorafenib alone. The toxicity of this combination is dominated by adverse events common to interferon that limit further development of this regimen.

Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC)

4502 Background: Treatment for advanced RCC remains poor, with meaningful responses in a small minority. Most pts with clear cell RCC have loss of VHL protein primarily due to gene mutation, result...

Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC)

4502 Background: Treatment for advanced RCC remains poor, with meaningful responses in a small minority. Most pts with clear cell RCC have loss of VHL protein primarily due to gene mutation, result...

Chemoimmunotherapy in the systemic treatment of advanced renal carcinoma

Polychemotherapy and immunomodulating treatment using IL-2 and/or IFN-alpha produce objective responses in a proportion of advanced renal cell carcinoma patients. The goals of an improved cost effectiveness and therapeutic index of interleukin-2 and/or Interferon-alpha in combination with chemotherapeutic agents require the design of risk factor adapted individual therapeutic strategies for the outpatient setting. High dose i. v. IL-2 therapy in metastatic renal cell carcinoma has been proven effective [11]. Other modalities of applying IL-2 have been described [12-14] (Table 1). A cumulative risk-score identified three risk-groups with significant differences in median survival [16]. The SC use of IL-2 and INF-alpha has been established in the treatment of RCC [16, 23]. It appears that combination chemoimmunotherapy including p. o. retinoic acid is far more effective than single agent treatment. Further studies will have to be designed to improve therapeutic index and cost effectiveness in systemic combination therapy in metastatic RCC.

Enhanced in vivo cytotoxicity of recombinant human tumor necrosis factor with etoposide in human renal cell carcinoma

The combination of tumor necrosis factor (TNF) and etoposide (ETP) was evaluated for potential cytotoxic efficacy against a human renal cell carcinoma xenograft using an in vivo assay employing an athymic mouse host with tumor implanted a the subrenal capsule site. Both antitumor efficacy (relative survival or RTS) and toxicity (weight loss) of TNF and ETP alone and in combination were evaluated. While TNF and ETP alone were mildly inhibitory (RTS 90% and 71%, respectively), the combination caused marked tumor inhibition (45% of controls). Host toxicity encountered with the combination did not exceed the toxicity associated with ETP alone, suggesting that the therapeutic index may have been augmented. It is concluded that enhanced antitumor activity without substantial augmentation of toxicity is observed with this combination, providing a rationale for further evaluation of tumor necrosis factor-based regimens for the treatment of advanced renal carcinoma.

Role of interferons in the therapy of metastatic renal cell carcinoma

The prognosis of metastatic renal cell carcinoma continues to be dismal because of the lack of effective systemic therapies. To date, existing chemotherapy and hormonal therapy have produced disappointing results. However, alpha interferon and other biologic response modifiers have recently shown evidence of modest but consistent activity. This review summarizes results obtained with alpha interferon alone or in combination in the treatment of advanced renal carcinoma. It is hoped that future development of this field of cancer therapy may result in further improvements in the clinical management of these patients.

Clinical trial of cisplatinum (NSC 119875) in metastatic renal cell carcinoma

Thirty-two patients with metastatic renal cell carcinoma were treated with cisplatinum, 100 mg./M 2 at twenty-eight-day intervals. The drug was given intravenously after first assuring adequate hydration. Response could be determined in 23 patients. There were no partial or complete responses, although 1 patient had less than a 50 per cent reduction in pulmonary lesions and 7 patients had stabilization of their disease for periods ranging from three to seven months. It is concluded that the therapeutic value of cisplatinum in the treatment of advanced renal carcinoma is negligible when used as a single agent.