Mariko Kambe

Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group.

PURPOSE A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. PATIENTS AND METHODS From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. RESULTS A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CONCLUSION CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.

Induction of p53-independent Apoptosis Associated with G2M Arrest Following DNA Damage in Human Colon Cancer Cell Lines

The tumor suppressor p53 protein induces apoptosis in response to various kinds of DNA damage in normal cells, but it is still unclear whether or not apoptosis induced by DNA damage correlates with the p53 status in tumor cells. We determined the status of p53 by functional analysis of separated alleles in yeast in five human colon cancer cell lines, SW‐480, SW‐620, DLD‐1, COLO320 and LS174T and investigated whether p53 is necessary for apoptosis and cell cycle arrest after treatment of the cells with a DNA‐damaging agent, etoposide (VP‐16), or γ‐irradiation. Of these cell lines, only LS174T expresses a functional p53. Apoptosis was detected in SW‐480 and COLO320 cell lines, but not in the other cell lines, including LS174T cell line with a normal p53 function. Furthermore, cell cycle analysis revealed accumulation in the G2M phase preceding induction of apoptosis in SW‐480 and COLO320 cells, but not in the other cells. These results suggest that apoptotic induction by DNA damage is not necessarily related to p53 status and that induction of p53‐independent apoptosis following DNA damage may correlate with G2M arrest in the cell cycle, at least in the colon cancer cell lines used in this study.

Anti-K-ras ribozyme induces growth inhibition and increased chemosensitivity in human colon cancer cells

Colon cancer is one of the carcinomas that is resistant to a variety of therapies. To develop a new therapy by regulating the activated K-ras gene in colon cancers, we prepared synthetic DNA encoding the ribozyme (catalytic RNA), and inserted it into an expression vector (LNCX) originated from a retrovirus. Transfection of the vector into SW620 human colon cancer cells brought about significant suppression of K-ras mRNA synthesis and inhibition of the cell growth. Studies in athymic mice, in which K-ras ribozyme-introduced SW620 cells were transplanted, also revealed a marked reduction of tumor growth in vivo. Furthermore, the ribozyme-introduced tumors became more sensitive to treatment with anti-cancer drugs such as cisplatin, adriamycin, 5-fluorouracil, vincristine, and etoposide. These data suggest that the possible efficacy of anti-K-ras ribozyme increases the chemosensitivity of human colon cancers as well as the inhibitory effect on the growth of human colon cancers.

Mechanism of Anti-tumor Effect of Combination of Bleomycin and Shock Waves

We have previously reported marked enhancement of the cytocidal effect of bleomycin (BLM) on cancer cell suspensions in vitro by the combination with shock waves. In this study, we evaluated the synergistic effects on cancer cell proliferation and apoptosis in solid tumors. A spherical piezoceramic element was used as the shock wave source, with a pressure peak of 40 MPa. A human colon cancer cell line, SW480 was implanted onto the back of nude mice. Two thousand shock waves were administered to the tumor immediately following an intravenous injection of BLM at a dose of one‐tenth of the LD50. The tumor was extirpated at 3, 6, 12, 24, 72 h and 1 week following shock exposure. Cell proliferation and apoptosis were detected by Ki‐67 using antibody MIB‐1 and by the terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP‐biotin nick‐end labeling (TUNEL) method. The lowest percentage (35.7%) of Ki‐67‐positive cells appeared 24 h following the treatment. The maximum apoptotic index was detected within 6 h following the treatment. Moreover, numerous large cells with enlarged nuclei were detected histologically. These results suggest that shock waves may enhance chemotherapeutic effects by increasing apoptosis and decreasing cell proliferation in the tumor tissue.

Enhancement of the efficacy of anticancer drugs with electroporation: Successful electrochemotherapy against gastric cancer cell lines in vivo and in vitro

BackgroundThe purpose of this study was to determine whether micropore formation caused by application of an electric current can increase the influx of anticancer drugs across cancer cell membranes with a concomitant increase in dose intensity and, therefore, toxicity to cancer cells.MethodsTwo cell lines, GCIY and KATO III, both established from human gastric cancers, were used as target cells to assess the effects of combining electroporation and anticancer drug therapy. Results were measured as the proliferation of cells to 50% of the value in control mice (IC50).ResultsWhen GCIY cells were used as targets in vitro, the IC50 value for bleomycin was decreased significantly by the electroporation, to 10−4 of the dose for the chemotherapeutic agent alone, and the IC50 values of cisplatin and 5-fluorouracil were decreased to one tenth of their baseline values. In the case of KATO III cells, the IC50 value for bleomycin was reduced by 10−2, but that of cisplatin did not change. The IC50 value for doxorubicin did not change when GCIY cells, showing multidrug resistance, or when KATO III cells, lacking multidrug resistance, were subjected to electroporation. When GCIY cells were transplanted subcutaneously into nude mice, the resultant tumors decreased to a minimum size at 2 weeks after combined treatment with bleomycin and electroporation.ConclusionElectroporation seems to be a promising adjunct to cancer chemotherapy.

Phase II Trial of S-1 plus Low-Dose Cisplatin for Unresectable and Recurrent Gastric Cancer (JFMC27-9902 Step2)

Aims: The efficacy and the toxicity of oral fluorouracil derivative S-1 plus low-dose cisplatin in unresectable or recurrent gastric cancer were evaluated by a phase II study. Methods: S-1 was administered orally for 28 days following 14 days’ rest at 80–120 mg/body/day, depending on body surface area. During administration of S-1, cisplatin was given twice a week at the recommended dose (10 mg/m2), which was determined by a phase I study. Data from 34 patients in phase II and 8 patients treated with the recommended dose of cisplatin in phase I were analyzed. The primary endpoint was objective response. Results: The response rate was 47.1%. The median survival time was 11.0 months and the median progression-free survival was 6.9 months. The grade 3/4 toxicities observed in 10% or more of the treated patients were neutropenia (16.7%), anemia (16.7%) and anorexia (11.9%). The serum concentration of cisplatin was 794 ± 341 ng/ml at day 25 of the first course. Conclusions: S-1 plus low-dose cisplatin may be a clinically useful regimen for unresectable or recurrent gastric cancer because of its infrequent adverse events in spite of considerable efficacy and its convenience of no hydration and no hospitalization.