Renal cancers

Sorafenib is a multitargeted cancer therapy that inhibits VEGFR, PDGFR, KIT, fetal liver tyrosine kinase 3 (FLT-3), and the serine/threonine kinase RAF. RAF kinase is a key downstream effector of Ras in the MAPK/Ras signal-transduction pathway that has been linked to various cancers. Sorafenib is both a tyrosine kinase inhibitor and serine/threonine signal-transduction inhibitor. Sorafenib has been approved in renal cancer. 

Sunitinib is also a multitargeted cancer therapy targeting VEGFR, PDGFR, KIT, FLT-3, and RET. Sunitinib has been approved in GIST refractory to imatinib and renal cancer. 

MEL A498, renal cancer EVSA-7, mammary cancer H226, lung cancer IGROV, ovarian cancer Ml 9, melanoma MCE-7, mammary cancer WiDr, colon cancer. 

Hypercalcemia occurs in 10% to 30% of patients with cancer during the course of their disease. The most common tumor types associated with hypercalcemia are breast cancer squamous cell carcinomas of the head, neck, and lung and renal cancer. 

Armstrong, B., Garrod, A., Doll, R., A retrospective study of renal cancer with special reference to coffee and animal protein consumption, BrJ Cancer 33, 127, 1976. 

In a historical cohort mortality study of 1,990 primary lead smelter workers, an SMR of 2.04 for mortality from renal cancer was calculated (Selevan et al. 1985). The cohort consisted of workers who had worked at least 1 year, with at least 1 day of employment at the smelter between 1940 and 1965. The cohort had been heavily exposed to lead and in 1976 the PbB levels averaged 56.3 pg/dL. Exposures to cadmium and arsenic were generally minor. A follow-up study of this cohort was conducted from 1977 through 1988 (Steenland et al. 1992). Analysis of the follow-up study revealed an excess of kidney cancer, particularly in the high-lead group (SMR 2.39). Although, as the authors indicate, the study is... 

The lead-induced nephropathy observed in humans and rodents shows a comparable early pathology (Goyer 1993). However, in rodents, proximal tubular cell injury induced by lead can progress to adenocarcinomas of the kidney (see Section 2.2.3.8). The observation of lead-induced kidney tumors in rats may not be relevant to humans. Conclusive evidence for lead-induced renal cancers (or any other type of cancer) in humans is lacking, even in populations in which chronic lead nephropathy is evident. 

Baker EL, GoyerRA, Fowler BA, etal. 1980. Occupational lead nephropathy and renal cancer. Am J IndMed 1 138-148. 

Lilis R. 1981. Long-term occupational lead exposure, chronic nephropathy, and renal cancer A case report. Am J Ind Med 2 293-297. 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Zhao Y, Ehara H, Akao Y, Shamoto M, Nakagawa Y, Banno Y, Deguchi T, Ohishi N, Yagi K, Nozawa Y (2000) Increased activity and intranuclear expression of phospholipase D2 in human renal cancer. Biochem Biophys Res Commun 278 140-143... 

Yang, J.C. et al., Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer, J Clin Oncol, 21, 3127, 2003. 

Bastide C, Garcia S, Anfossi E, Ragni E, Rossi D (2006) Histologic evaluation of radiofrequency ablation in renal cancer. European Journal of Surgical Oncology 32 980-983. 

Boni IP, Leister C, Bender G Fitzpatrick V, Twine N, Stover J, Domer A, Immermann F, Burczynski ME. (2005) Population pharmacokinetics of CCI-779 Correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther 77 76-89. 

Kidney Tubular cells Low MW proteins (Lysozyme) Rat, man Nephrotic syndrome Renal cancer... 

Based on a combination of available human case studies and experiments with laboratory animals, the major public health concerns associated with exposure to 1,4-dichlorobenzene are effects on the liver, kidneys, and blood. Some immunological, dermatological, and neurological effects have also been reported in exposed humans. There is information from animal studies which raises the question of whether 1,4-dichlorobenzene can cross the placenta and elicit structural effects on the developing fetus. Data from a study conducted in rats using the intraperitoneal route have demonstrated sperm abnormalities. Cancer of the liver as a result of lifetime exposure to 1,4-dichlorobenzene has been shown in mice, and renal cancer has been reported in male rats. However, recent studies related to the mechanism of renal carcinogenesis in rats suggest that these tumors may not be expected to occur in exposed humans. Issues relevant to children are explicitly discussed in Section 2.6, Children s Susceptibility, and Section 5.6, Exposures of Children. 

Animal data include a 76-week inhalation study in rats that did not result in cancer (Riley et al. 1980), a 2-year oral study in rats that resulted in renal cancer in males (NTP 1987), and a 2-year study in mice that resulted in liver cancer (NTP 1987). No data using the dermal route were located. Additional data via the inhalation route would be useful since chronic inhalation exposures to 1,4-dichlorobenzene in the air of the home and the workplace are the main sources of human exposure to this compound. No further studies via the oral route appear to be necessary at this time. Chronic-duration cancer studies via the dermal route may be useful since chronic dermal contact with 1,4-dichlorobenzene at low levels in drinking water occurs in several U.S. communities. 

A few studies have reported an association between bladder and renal cancers and occupations having the potential for exposures to asphalt. In an historical cohort study of 1320 workers in the asphalt industry, there was a significant increase in brain cancer [standardized mortality ratio (SMR) 500] but not in respiratory, bladder, or gastrointestinal cancer. Of 679 Danish men who were heavily exposed to asphalt, significant increases occurred in the incidences of cancer of the mouth (SMR 1111), esophagus (698), rectum (318), and lung (344). ... 

It does not appear that the nephrotoxicity attributable to a2u-globulin syndrome is relevant to humans. Most epidemiological studies have not shown an association between gasoline exposure and renal cancer risk. However, a recent case-control study from Finland reported a significant association between renal cell cancer and gasoline that was dose dependent."... 

Toxicology. Hexachlorobutadiene (HCBD) causes kidney damage including renal cancer in experimental animals it also produces central nervous system effects and causes hepatic disorders at very high concentrations. 

Phase II clinical trials of Pazopanib were initiated in November 2004 in patients with RCC [309]. Subsequently, GlaxoSmithKline initiated a phase II trial in patients with NSCLC in the USA, Europe, and Israel. By April 2006, phase III trials had started in patients with advanced/metastatic renal cancer. 

Hexachlorobutadiene did not adversely affect reproduction in animals except at high doses (150 mg/kg/day for 10 weeks). Although there was some evidence of fetotoxicity in animals after inhalation (10 ppm) or oral (15 mg/kg/day) exposure, embryolethality and teratogenicity were not detected. Oral studies in animals indicate that hexachlorobutadiene may increase the risk of renal cancer at dose levels of 20 mg/kg/day. The effects of hexachlorobutadiene are most pronounced after repeated chronic exposure to low doses, suggesting that effects are cumulative. For this reason, there is greater concern for populations living near hazardous waste sites, where exposure to low levels may occur for long periods of time, than for acute exposure scenarios. 

Administration by experienced physician only pts should be hospitalized for 1st course d/t risk for severe Rxn Uses G1 adenoma, liver, renal cancers colon pancreatic CAs Action Converted to 5-FU inhibits thymidylate synthase DNA synth (S-phase specific) Dose 0.1-0.6 mg/kg/d for 1-6 wk (per protocols) usually intra-arterial for liver mets Caution [D, -] Interaction w/ vaccines Contra BM... 

Renal cancer, also referred to as Grawitz s tumor or hypernephroma, is a tumor derived from the proximal tubules of the kidney and accounts for approximately 3% of adult malignancies. 

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