chromomycin-a3 and Kidney-Neoplasms

Late-stage clear cell renal carcinoma poses a formidable clinical challenge due to the high mortality rate associated with this disease. Molecular and genetic studies have identified functional loss of the von Hippel-Lindau (VHL) gene as a frequent and crucial event in the development of the malignant phenotype of clear cell renal carcinomas. Loss of VHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. The objective of this study was to evaluate the possibility of targeting VHL loss through pharmacologic means. Chromomycin A3 (ChA3) was identified through in silico analysis of existing publicly available drug profiles from the National Cancer Institute as an agent that seemed to selectively target VHL-deficient clear cell renal carcinoma cells. Genotype-selective toxicity was first determined through short-term viability assays and then confirmed with clonogenic studies. Coculture of fluorescently labeled VHL-deficient and VHL-positive cells showed discriminate killing of the VHL-deficient cells with ChA3. Mechanistically, overexpression of hypoxia-inducible factor (HIF)-2alpha in VHL-positive clear cell renal carcinoma cells phenocopied loss of VHL with respect to ChA3 toxicity, establishing ChA3 as a HIF-dependent cytotoxin. This study shows the feasibility of selectively targeting the loss of the VHL tumor suppressor gene in clear cell renal carcinoma for potential clinical benefit and may have greater ramifications in the development of new targeted therapies for the treatment of cancer and other genetic diseases.

Topics: Algorithms; Animals; Antibiotics, Antineoplastic; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Carcinoma, Renal Cell; Cell Line, Tumor; Chromomycin A3; Drug Delivery Systems; Drug Screening Assays, Antitumor; Humans; Kidney Neoplasms; Von Hippel-Lindau Tumor Suppressor Protein

A study was made of the relationship between post-operative chemotherapy and metastasis and recurrence of bladder tumor in 9 patients with renal pelvic and ureteral tumors. Within 6 months on average, post-operative metastasis was found in 33.3% (3 out of 9 cases). Differentiating according to the type of chemotherapy, the rate of occurrence of metastasis was 50% (2 out of 4) in the case of treatment with either a combination of FT-207, chromomycin A3 and cytosine arabinoside, or with FT-207 alone, while it was 100% (2 out of 2) in stage pT2 and pT3 patients. For combined administration of CDDP, FT-207 and cytosine arabinoside, or for that of CDDP and neocarzinostatin, on the other hand, the rate of occurrence of metastasis was only 20% (1 out of 5) in stage pT2 and pT3 patients, while CDDP administration was found to be effective for preventing post-operative metastasis. However, while recurrence of bladder tumor was found in a total of 3 out of 9 cases (33.3%), recurrence occurred in 40% (2 out of 5) of the cases treated with CDDP. The administration of CDDP was therefore not found to be effective for preventing recurrence of bladder tumor.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromomycin A3; Cisplatin; Cytarabine; Humans; Infusions, Parenteral; Kidney Neoplasms; Kidney Pelvis; Male; Middle Aged; Neoplasm Metastasis; Postoperative Care; Tegafur; Ureteral Neoplasms; Urinary Bladder; Urinary Bladder Neoplasms