Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells.

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.

Production and antiproliferative activity of liposomes containing the antitumour drug chromomycin A3.

In the present paper the production and characterization of liposomes are described as a specialized drug delivery system for chromomycin. Liposomes were prepared by the reverse phase evaporation technique followed by extrusion through polycarbonate filters; afterwards the vesicles were characterized in terms of dimensions, morphology and encapsulation efficacy. The aim of this work was to produce a drug delivery system able to reduce the toxicity problems related to the administration of this drug. The analysis of the in vitro antiproliferative activity on cultured human leukemic K562 cells demonstrated that ionic and neutral liposomes containing chromomycin are 1.5 and 7-fold more effective respectively as compared to the free drug. Based on these results and taking into account the increased solubility of the drug in this system, liposomes could represent a promising drug delivery system for use in the experimental therapy using chromomycin.

Breast cancer developing after chemotherapy for osteosarcoma: a case report.

A 24-year-old patient who developed breast cancer 16 years after chemotherapy for osteosarcoma is presented. She had no family history of cancer. She had also not had radiotherapy. She had been given chemotherapy consisting of VAOMT (vincristine 10.2 mg, cyclophosphamide 900 mg, mitomycin C 15.2 mg, chromomycin A3 25.8 mg) pre- and post-operatively in the treatment of her osteosarcoma. Careful long-term follow-up is required after treatment of malignant neoplasms because there is a possibility of developing a second malignancy.

Induction of natural killer (NK) activity in mice by injection of chromomycin A3.

Intravenously or intraperitoneally administered Chromomycin A3 (CHRM), an anticancer drug, augmented natural killer (NK) activity of both spleen cells and peritoneal exudate cells in BALB/c mice. When CHRM was administered intravenously, NK activity increased to about five fold that in nontreated mice on the 3rd to the 5th day, then rapidly decreased by the 7th day. On the other hand, when CHRM was administered by the intraperitoneal route, a peak of increased NK activity was observed on 5th to 7th day followed by a more gentle decrease. Augmentation of NK activity by CHRM was enhanced by additional administration of Interferon- gamma (IFN-gamma). Experimental evidence that NK activity could be augmented by CHRM in various strains of mice, independent of H-2 haplotype, suggested that involvement of genetic control within class I region of major histocompatibility complex could be excluded. When BALB/c mice inoculated subcutaneously with Meth A cells were treated with i.p. injection of CHRM, or CHRM in combination with IFN-gamma, the growth of the tumor cells was inhibited, indicating in vivo significance for the increased NK activity. Since this inhibitory effect was decreased by the injection of anti Asialo GM1 antibody (alpha-ASGM1), the effector cells presumably exerting killing activity against Meth A cells were concluded to be Asialo GM1 antigen positive.

[Adverse reactions to carcinostatics and countermeasures].

As adverse reactions to the combination treatment by the digestive system, we observed the occurrence of nausea and vomiting in 15% of the cases who received FTP treatment consisting of 5-FU, toyomicin and prednisone, 25% of the cases who received MFU treatment consisting of MMC, 5-FU and ACNU, and in 64% of the cases who received PPQ treatment consisting of CDDP, Carboquone (CQ) and prednisone. The antiemetics usually used are metoclopramide and droperidol, and we preadminister valproate preparation when persistent and delayed emesis is predicted. Several randomized trials have been made, and good efficacies with drugs such as metoclopramide, domperidone and steroid have been reported. Efficacy was good with acute emesis, but nonexistent with delayed emesis. As to the liver injury, in our combination treatment, only one case showed elevation of GPT by more than 500 units in the cases treated with MFU, while, increase in liver enzymes in the blood was observed in 10-20% of the cases. Similarly, there were not so many cases of liver injury during PPQ treatment. Thus, liver injury due to carcinostatic would be less frequent. Moreover, autopsy revealed hepatocellular-type of liver injury, cholestatic type liver injury and fatty metamorphosis at reasonable incidence. There were no typical cases of veno-occlusive disease which are noticed recently. The most important point for prevention and countermeasures against liver injury is to be careful not to use the previously mentioned drugs exhibiting toxicity in the liver if hepatic disease exists.

[Benefits of cisplatin-based polychemotherapy in non-small cell bronchogenic carcinoma. Kyushu Lung Cancer Chemotherapy Study Group].

We studied the efficacy of cisplatin-based polychemotherapy for non-small-cell lung cancer. One hundred nineteen patients with adenocarcinoma or large cell carcinoma were randomized to receive cyclophosphamide, adriamycin, cisplatin and mitomycin C (CAPM) or mitomycin C, cytosine arabinoside and tegafur (MCT), and 48 patients with squamous cell carcinoma were randomized to receive cisplatin, adriamycin and peplomycin (PAP) or mitomycin C, cyclophosphamide, tespamine, toyomycin and tegafur (MCTTT). Radiation was given to the chest in patients with stage I-III disease. The response rates were CAPM, 34.5%; MCT, 13.1% (p less than 0.01) and PAP, 63.3%; MCTTT, 42.3%. A significant difference in response rate between the CAPM and MCT regimens was observed only in stage IV patients and not in stage I-III patients. The median survival was 9.5 months in the CAPM arm vs. 6.5 months in the MCT arm (p less than 0.007), and 8.5 months in the PAP arm vs. 6.5 months in the MCTTT arm. Improved median survival for the CAPM regimen was noted only in stage IV patients and not in stage I-III patients when compared to patients given the MCT regimen, respectively. Nausea and vomiting were significantly increased in patients with cisplatin-based polychemotherapy. Myelosuppression was more severe with the CAPM regimen than with the other chemotherapy regimens. We concluded that cisplatin-based polychemotherapy, CAPM and PAP therapy were of more benefit to patients with disseminated non-small-cell lung cancer than MCT and MCTTT therapy.

[A study of post-operative chemotherapy for renal pelvic and ureteral tumors].

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.

[Chemotherapy of gastric and rectal cancers incorporating non-radical irradiation during remission induction. 1].

For the remission induction therapy of advanced gastric and rectal cancer, 25 cases were treated by non-radical irradiation (total doses: 3000-6000 rad) combined with tegafur, which minimized the tumor mass. For the reduction of tumor mass, a modified method of FAMT was employed and for the maintenance therapy of long-term chemotherapy a modified method of FAMT, MFE, MF or tegarfur alone were performed. Prolongation in survival was obtained with this combination therapy: Of 25 cases, 11 cases survived longer than one year and 6 cases longer then two years. One case of survived rectal cancer obtained disease-free for about 8 years with this treatment. But the observation period was too short to calculate one-year and two-year survival rates of all cases. The indications for application of this combination therapy were as follows; (1) Locally operable cases with myocardial infarct, heart insufficiency, poor risk or refusal of operation, (2) Very aged patients, (3) Locally inoperable cases without clinical metastasis, and (4) Primary lesion of gastric cancer with small metastasis controllable by tegafur. It was concluded that over 3000 rad of irradiation combined with tegafur was necessary to obtain the sufficient radiation effect. As for side effects, loss of appetite , leukopenia and a few case of gastric bleeding by radiation were noted. From the result this treatment modality appears to be valuable in the management of gastric and rectal cancer.

[Clinical trial of carmofur (HCFU) in the treatment of malignant ovarian cancer--The first report: combination therapy with endoxan, mitomycin C, and toyomycin].

A new fluoropyrimidine antitumor agent, carmofur (HCFU, Mifurol) was administered to patients with malignant ovarian tumor. Two of these patients revealed favorable results. The first patient was a 72-year-old female, who was diagnosed as having ovarian serous cystadenocarcinoma with metastatic omental tumor at exploratory laparotomy, its size was newborn child head size. She was started on with a combination chemotherapy of Mifurol (600 mg p.o. daily), Endoxan (4 mg/kg i.v. twice a week), Mitomycin C (0.04 mg/kg i.v. twice a week) and Toyomycin (0.01 mg/kg i.v. twice a week). After four weeks, this combination therapy brought her a complete response with disappearance of pleural effusion, ascites and metastatic tumor. The second case was a 39-year-old female, who underwent adnexectomy elsewhere which led to the discovery of Krukenberg tumor, and was referred to our hospital. After the first course of the same combination chemotherapy, second look operation was performed. Histological examination of the specimen obtained by metastatic tumor of uterosacral ligament showed the degeneration (grade II b-III, Oboshi and Shimozato) of cancer cell. It is suggested that this combination chemotherapy including Mifurol is effective and useful for the patients with ovarian carcinoma.

[In vitro experiment on combination effect of chromomycin A3 and amphotericin B (author's transl)].

The combination effect of chromomycin A3 and amphotericin B against HeLa cells and Bacillus subtilis ATCC 6633 by the agar plate diffusion and the serial dilution method was examined. As a result, evident synergistic effect was observed when the HeLa cell was used as the test cell.