Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents.

BACKGROUND: The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents. METHODS: We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome. RESULTS: The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status. CONCLUSIONS: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.

Results of two sequential phase II studies of interleukin-2 (IL2) in metastatic renal cell carcinoma and melanoma: high-dose continuous intravenous IL2 infusion and subcutaneous IL2 administration in combination with alpha interferon.

The results of two sequential trials, the first one with high dose interleukin 2 (IL2) by continuous intravenous infusion and the second one with subcutaneous IL2 and alpha-interferon (alpha IFN), performed in consecutive patients with metastatic melanoma and renal carcinoma at the Clinica Universitaria de Navarra are presented. In the high-dose continuous IL2 trial, recombinant IL2, 18 x 10(6) IU/m2, was administered daily by continuous infusion five days a week for two weeks, and the treatment cycle was repeated after a rest of 2 weeks. Twenty two patients were treated and objective responses were observed in 3 (13.3%). Toxicity was frequent and severe, and all but one required dose reduction. The mortality rate was 9% (2/22). In the subcutaneous IL2 and alpha IFN trial, subcutaneous IL2, 4.8 x 10(6) IU/m2, was administered daily, five days a week, for 3 consecutive weeks. IL2 dose was given every 8 hours on the first day and every 12 hours on the second day, as a loading induction dose. Concomitant alpha-IFN, 3 x 10(6) IU/m2 was given subcutaneously once a day on days 1, 3 and 5 weekly each week for the duration of IL2 therapy. Of the 24 patients treated with this combination, 3 partial responses were noticed (12.5%) and the toxicity was mild to moderate. These results suggest that both, IL2 alone or IL2 in combination with alpha-IFN are minimally active and that any improvement in tolerance might impair its antitumor activity.

Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-Hodgkin's lymphomas.

T cells infiltrating (T-TIL) B cell non-Hodgkin's lymphomas (NHL) are thought to represent a local host response to the tumor. However, tumor progression in the presence of this T cell infiltrate suggests that the T-TIL may be functionally impaired. To address this issue we determined whether response to stimulation of T-TIL from 25 patients with NHL through the T cell receptor (TCR/CD3) and the interleukin-2 (IL-2) receptor (IL-2R) was intact, since activation of these receptors is important for proliferation and cytokine production. Our results demonstrate defects in response to stimulation via TCR/CD3 and the IL-2R in T-TIL cells from patients with NHL that were not observed with T cells from the peripheral blood. T-TIL showed minimal proliferation to anti-CD3 and only modest proliferation to IL-2 alone or when combined with anti-CD3. Moreover, cytokine production in T-TIL was impaired since stimulation through the TCR/CD3 complex did not induce mRNA for interferon gamma (IFN gamma), IL-2, IL-4 or IL-10. The functional unresponsiveness of these cells may be linked to altered signalling through the TCR/CD3 since an abnormal tyrosine phosphorylation pattern was detected in T-TIL after stimulation with anti-CD3.

Intra-arterial hepatic treatment with carboplatin (CBDCA) and 5-fluorouracil (5-FU) in metastases from colorectal carcinoma.

Thirty-one patients with hepatic metastases from colorectal carcinoma were treated with carboplatin (CBDCA), 55 mg/m2, given in a 4-hour intra-arterial infusion daily for 5 days, and 5-fluorouracil, 900 mg/m2, given in a 20-hour intra-arterial infusion daily for 5 days. Cycles were administered every 5 weeks. Objective responses were observed in 16 (51.6%) patients (5 complete and 11 partial responses). Another 13 patients maintained stable disease, and 2 patients rapidly progressed. The overall median survival was 23.5 months. The 16 patients with objective response had a median survival of 26.5 months. In this series, no evidence of biliary sclerosis, cholecystitis, chemical hepatitis, or myelosuppression was observed. Complications of drug delivery system were observed in 14 (45.16%) patients. In conclusion, intra-arterial hepatic chemotherapy with CBDCA-5FU was associated with a modest benefit, expressed in good quality responses and extended survival of approximately 2 years in about half of the treated patients.

Urokinase combination chemotherapy in small cell lung cancer. A phase II study.

BACKGROUND AND METHODS: Fifty-one patients with small cell lung cancer (SCLC) were treated with alternating urokinase (UK)-cyclophosphamide-doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-vincristine and cisplatin-etoposide-vincristine. UK was given as a loading dose of 3000 micrograms/kg body weight, followed by 3000 micrograms/kg/h for 6 hours. Thoracic irradiation with split technique (46 Gy) and prophylactic cranial irradiation (25 Gy) were administered to responding patients. A second staging was performed in patients exhibiting a clinical complete response (CR) after 1 year. RESULTS: In 27 patients with limited disease, there were 23 CR and 8 partial responses (PR) (CR, 85.1%; 66.2-95.8% at 95% confidence intervals); in 24 patients with extensive disease, there were 17 CR, 4 PR, and 3 cases with progression. Pathologically proven CR were observed in 59.2% patients with limited disease and 33.3% patients with extensive disease. Survival rates were as follows: in patients with limited disease, 1 year, 85.1%; 2 years, 55.5%; and 3 years, 25.9%; in patients with extensive disease, 1 year, 54.1; and 2 years, 16.9%. Median survival times were 26.3 months (patients with limited disease) and 13.3 months (patients with extensive disease). UK-related toxic effects included four episodes of mild to moderate bleeding, one allergic reaction, and one cerebrovascular accident. Myelotoxicity was severe, with a median of two episodes of Grade III-IV (World Health Organization classification) aplasia per patient. CONCLUSIONS: These results are consistent with a potential benefit of fibrinolytic therapy in combination with chemotherapy in patients with SCLC with limited disease. Additional trials are indicated.

Carboplatin (CBDCA), 5-fluorouracil (5-FU) and mitoxantrone (DHAD): an effective and well tolerated regimen for metastatic breast cancer.

Fifty-five women with metastatic breast cancer were treated with carboplatin (CBDCA), 55 mg/m2 i.v. bolus, daily for 3 days, 5-fluorouracil (5-FU) 900 mg/m2, (max. dose 1,500 mg/day in 24-h infusion (Travenol system) daily for 3 days, and mitoxantrone (DHAD) 8 mg/m2, i.v. bolus on day 1. Cycles were administered every 5 weeks. Objective responses were observed in 25 (44%) patients (95% confidence interval: 28%-60%) with a median duration of remission of 11.5+ months (range 6.5(+)-31+). Toxicity was mild. These results reflect the fact that combination of CBDCA, 5-FU and DHAD is effective and very well tolerated as an outpatient regimen.

[Intra-arterial chemotherapy, using the hepatic artery, in metastases of colorectal carcinoma]. / Quimioterapia intra-arterial hepática en las metástasis del carcinoma colorrectal.

Hepatic metastasis is the major cause of death in advanced cancer of the colon and rectum. Various modes of therapy have been attempted with only partial success. Infusion of cytotoxic agents into the hepatic artery has allowed a higher concentration of drug into the tumor capillary bed than is achievable with intravenous administration. We review the data on therapeutic outcome, administration techniques and toxicity of hepatic arterial chemotherapy for colorectal cancer metastatic to the liver.

Phase I trial of intermittent high-dose dacarbazine.

A phase I study was conducted with dacarbazine (DTIC) protected from light and administered iv as a single dose every 3 weeks. Eighteen patients received 47 courses of DTIC, with doses ranging from 850 to 1980 mg/m2. Hypotension was the dose-limiting toxic effect and it may be secondary to the citric acid present in the pharmaceutic preparation of DTIC. Sporadic myelosuppression was seen at doses greater than 1380 mg/m2. Other side effects noted were nausea and vomiting, acute diarrhea, headache, a "flu-like" syndrome, and a hypersensitivity reaction to sunlight. No antitumor activity was found. The results of this study indicate that this may be a qualitatively different way of giving DTIC, and that the side effects of this drug may be intermingled with those of citric acid in this particular schedule. If the conventional pharmaceutic preparation of this drug is not modified, further studies with high-dose DTIC protected from light should be discouraged.