pirarubicin and Carcinoma--Renal-Cell

The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Cycle; Chronotherapy; Circadian Rhythm; Cisplatin; Doxorubicin; Endometrial Neoplasms; Female; Floxuridine; Genital Neoplasms, Female; Humans; Kidney Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Rats; Urinary Bladder Neoplasms; Urogenital Neoplasms

Enteropathy-associated T-cell lymphoma (EATL), an intestinal tumor of intraepithelial T lymphocytes, is a rare and highly aggressive disease. We herein describe a case of type II EATL with massive pyoid ascites in which a histological examination could not be performed despite emergency laparotomy that was successfully diagnosed using flow cytometry and the cell block technique to analyze the celomic fluid. This case suggests that EATL should be included in the differential diagnosis of pyoid ascites of unknown origin and that flow cytometry and the cell block technique of assessing celomic fluid are useful procedures for diagnosing EATL, especially in cases in which conducting a histological examination is impossible.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma, Renal Cell; Cyclophosphamide; Doxorubicin; Emergencies; Enteropathy-Associated T-Cell Lymphoma; Fatal Outcome; Female; Flow Cytometry; Humans; Intestinal Perforation; Kidney Neoplasms; Laparotomy; Multiple Organ Failure; Neoplasms, Second Primary; Nephrectomy; Omentum; Pleural Effusion; Prednisolone; Respiration, Artificial; Respiratory Insufficiency; Vincristine

Lexatumumab, a human agonistic monoclonal antibody against tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor-2 (TRAIL-R2), is a promising molecular-targeted therapeutic agent. Our past study indicated that low concentrations of doxorubicin sensitized renal cell carcinoma (RCC) cells to lexatumumab-mediated apoptosis. The present study was designed to examine the cellular and molecular effects of lexatumumab and anthracyclines in RCC cells. The treatment of human RCC cells with lexatumumab in combination with anthracyclines, epirubicin, and pirarubicin had a synergistic cytotoxicity. A marked synergistic apoptosis was induced by lexatumumab in combination with epirubicin or pirarubicin. Epirubicin and pirarubicin significantly increased the TRAIL-R2 expression at both the mRNA and the protein levels. The combination-induced cytotoxicity was significantly suppressed by the human recombinant DR5:Fc chimeric protein. To further explore the molecular mechanisms in this synergistic cytotoxicity with lexatumumab and anthracyclines, the changes in 84 apoptosis-related genes were evaluated by a quantitative polymerase chain reaction (PCR) array. Among these genes, 18 (CD40LG, FASLG, LTA, TNSF7, FAS, BAG3, BAK1, BAX, BID, BIK, BCL10, caspase-1, caspase-5, caspase-6, caspase-10, TNF receptor-associated factor 1, PYCARD, and CIDEA) were significantly upregulated and eight (TNF receptor-associated factor 4, TNFRSF11B, TNF, BCL2, BCL2L1, BNIP3L, caspase-9, and DAPK1) were downregulated at mRNA levels in RCC cells cotreated with lexatumumab and epirubicin. Furthermore, the upregulation of mRNA levels of PYCARD and CIDEA was confirmed using real-time reverse transcriptase-PCR analysis. The present study demonstrates that anthracylines sensitize RCC cells to lexatumumab-mediated apoptosis by inducing TRAIL-R2 expression, and the utility of PCR array to elucidate the mechanism of synergistic apoptosis.

Topics: Anthracyclines; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Caspases; Cell Line, Tumor; Doxorubicin; Drug Synergism; Epirubicin; Humans; Kidney Neoplasms; Polymerase Chain Reaction; Receptors, TNF-Related Apoptosis-Inducing Ligand

Anti-Fas monoclonal antibody (mAb) kills Fas-expressing cells by apoptosis. Several anticancer agents also mediate apoptosis and may share common intracellular pathways leading to apoptosis with Fas. Thus, we reasoned that combination treatment of drug-resistant cells with anti-Fas mAb and drugs might overcome their resistance. We investigated whether anticancer agents enhance Fas-mediated apoptosis and cytotoxicity against renal cell carcinoma (RCC) cells. Treatment of ACHN RCC cells with anti-Fas mAb in combination with 5-fluorouracil, vinblastine, IFN-alpha, or IFN-gamma did not overcome resistance to these agents. However, combination treatment with anti-Fas mAb and Adriamycin (ADR) resulted in a synergistic cytotoxic effect. Furthermore, synergy was also obtained even when the exposure time was shortened from 24 h to 8 or 2 h. Synergy was also achieved in four other RCC cell lines and five freshly derived human RCC cells. Treatment with anti-Fas mAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on ACHN cells. Similar results were achieved with a combination of humanized anti-Fas mAb and ADR. Incubation of ACHN cells with ADR augmented the expression of Fas and p53, but not Bcl-2, Bax, or caspase-3. However, the activity of caspase-3 itself was apparently enhanced after treatment with ADR alone or combined treatment with anti-Fas mAb. The synergy obtained in cytotoxicity with anti-Fas mAb and ADR was also achieved in apoptosis. Exposure of ACHN cells and freshly derived RCC cells to ADR enhanced their susceptibility to lysis by peripheral blood lymphocytes and tumor-infiltrating lymphocytes. This study demonstrates that combination treatment of RCC cells with anti-Fas mAb and ADR might overcome their resistance. The sensitization required a low concentration of ADR and a short exposure time, thus supporting the potential in vivo application of a combination of ADR and anti-Fas mAb or immunotherapy in the treatment of ADR- and/or immunotherapy-resistant RCC.

Topics: Acridine Orange; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; bcl-2-Associated X Protein; Carcinoma, Renal Cell; Caspase 3; Caspases; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Epirubicin; fas Receptor; Fluorescent Dyes; Fluorouracil; Humans; Immunohistochemistry; Interferon-alpha; Interferon-gamma; Kidney Neoplasms; Lymphocytes, Tumor-Infiltrating; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Time Factors; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Vinblastine

We evaluated the usefulness of in vitro tumor culture system using a specialized collagen gel matrix (CGM assay) as a chemosensitivity test.. Chemosensitivity results of CGM assay were compared with other in vivo and in vitro assays on an implantable murine bladder tumor cell line (MBT-2). In addition we investigated the possibility of the clinical use of CGM assay using clinical specimens obtained from urogenital malignant tumor patients by comparing the result with that of the other chemosensitivity test, SDI testing using single cells (conventional SDI test). Methods of CGM assay were as follows. Tumor tissues on the collagen gel matrices were incubated under the existence of anticancer drugs following 4 days preculture. Drug sensitivities were evaluated by counting the number of viable cells adjusted to the tumor weight.. Inhibition rates in MBT-2 were high in the order of mitomycin C, cisdiamminedichloroplatinum (II), (2"R)-4'-0-tetrahydropyranyl adriamycin. Four of 6 anticancer drugs were decided as chemosensitive drugs. These results corresponded to the results of the antitumor effects on subcutaneously transplanted MBT-2 in vivo, moreover was correlated well with those of the conventional SDI test. Twenty of 22 cases, including 11 of 13 bladder cancer cases, 1 of 3 renal cancer cases, 2 of 3 testicular cancer cases and 1 of 1 adrenal cortical cancer cases, were evaluable in the clinical study of the CGM assay. Corresponding rates between the results of the CGM assay and those of the conventional SDI test performed simultaneously in 12 cases were excellent for each anticancer drug.. This CGM assay can serve as an effective tool for chemosensitivity testing because of its convenience and high evaluable rate.

Topics: Animals; Antineoplastic Agents; Bleomycin; Carcinoma, Renal Cell; Cisplatin; Collagen; Culture Media; Doxorubicin; Drug Screening Assays, Antitumor; Etoposide; Female; Humans; Kidney Neoplasms; Mice; Mice, Inbred C3H; Mitomycin; Urinary Bladder Neoplasms; Vinblastine

A 67-year-old man, who was nephrectomized due to renal cell cancer 4 years ago, was admitted to examine a mass shadow in the right middle lung field. He was diagnosed as small cell lung cancer with TBLB. Because of impaired renal function, he was treated with CBDCA (300 mg/m2, day 1), THP (30 mg/m2, day 1) and oral etoposide (25 mg/body, for 21 days) without any renal complications. After 3 courses of chemotherapy, the lung CT showed scar lesion despite the disappearance on the chest X-ray, and a right lower lobectomy was performed. Malignant cells remained in the scar lesion, but not in the lymph nodes. These findings suggested the effectiveness of neoadjuvant chemotherapy. This newly-designed chemotherapy procedure is necessary for patients with renal complications.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Renal Cell; Carcinoma, Small Cell; Chemotherapy, Adjuvant; Doxorubicin; Etoposide; Humans; Lung Neoplasms; Male; Neoplasms, Second Primary; Nephrectomy

We report a case of left renal cell carcinoma extending into vena cava with malignant peritoneal mesothelioma. A 41-year-old man presented to our outpatient clinic with macroscopic hematuria. Upon laparotomy, numerous white nodules were identified on diaphragm and serosa of liver, stomach, small intestine and mesentery. Biopsied specimen showed malignant mesothelioma of peritoneum and renal cell carcinoma of left kidney. He was treated with intraperitoneal cisplatinum and intravenous pirarubicin for mesothelioma, and chemoembolization for renal tumor. After two courses of therapy, he suffered from disseminated intravascular coagulation and died of subarachnoid hemorrhage. Autopsy revealed that intraperitoneal nodules were markedly decreased in number and renal tumor had changed into hemorrhagic necrosis, but tumor thrombus in vena cava had little necrotic change.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cisplatin; Doxorubicin; Embolization, Therapeutic; Humans; Kidney Neoplasms; Male; Mesothelioma; Neoplasms, Multiple Primary; Peritoneal Neoplasms

Twenty milligrams of (2"R)-4'-O-tetrahydropyranyladriamycin (THP) was administered intravenously to 14 patients with renal cell carcinoma and 11 with urinary bladder tumor at the start of surgery. Heparinized peripheral blood samples were collected at regular intervals and separated into plasma and blood cell fractions by centrifugation for the estimation of the THP concentration. The THP concentrations in the surgical specimens were also studied. In the tissue of renal cell carcinoma, the nuclear fraction was obtained by fractionation in order to estimate the THP concentration. The THP concentrations of the plasma and blood cell fractions in both renal cell carcinoma and urinary bladder tumor gradually decreased with the lapse of time after administration. In renal cell carcinoma, grade 3 tumors revealed lower tissue and nuclear concentrations of THP than those of grade 1 and 2 tumors. Likewise, the tissue and nuclear concentrations of high-stage tumors were lower than those of low-stage tumors. On the other hand, in urinary bladder tumors, the THP concentrations in the tumors were found to be higher than those in normal urinary mucosa and muscle.

Topics: Carcinoma, Renal Cell; Combined Modality Therapy; Doxorubicin; Humans; Infusions, Intravenous; Kidney Neoplasms; Urinary Bladder Neoplasms

Each of 5 patients with renal cell carcinoma and urinary bladder tumor who were operated on at the department of urology, Hamamatsu University School of Medicine and its affiliated hospitals, received 20 mg of 4'-O-tetrahydropyranyladriamycin (THP) intravenously at the beginning of surgery. Heparinized peripheral blood samples were collected at regular intervals and separated in plasma and blood cell fractions by centrifugation for the estimation of THP. The THP concentration of the surgical specimen was also studied. In renal cell carcinoma, the surgical specimen was divided into cytoplasm and nuclear fractions, and the THP concentration in each fraction was measured. The THP concentration gradually decreased in the plasma and blood cell fractions with passage of time after the administration in both renal cell carcinoma and urinary bladder tumor. In renal cell carcinoma, although the tumor revealed a lower concentration of THP compared with the normal renal cortex and medulla, the nuclear fraction of the tumor showed a higher concentration than those of the normal renal cortex and medulla. In contrast to renal cell carcinoma, the THP concentration of the urinary bladder tumor was found to be higher than those of the normal urinary bladder mucosa and muscle.

Topics: Carcinoma, Renal Cell; Chromatography, High Pressure Liquid; Doxorubicin; Humans; Injections, Intravenous; Kidney Neoplasms; Tissue Distribution; Urinary Bladder Neoplasms