Search

5-Fluorouracil (5-FU) is a pyrimidine antimetabolite active against colorectal carcinoma and other malignancies of the digestive tract. Over-expression or mutation of thymidylate synthase (TS), the target enzyme of the 5-FU metabolite, 5-fluorodeoxyuridine monophosphate, is strictly correlated with cancer cell resistance to 5-FU. On this basis we investigated whether TS is a potential target for active specific immunotherapy of human colon carcinoma, which acquires resistance to 5-FU. Three TS-derived epitope peptides which fit defined amino acid consensus motifs for HLA-A2.1 binding were synthesized and investigated for their ability to induce human TS-specific cytotoxic T cell (CTL) responses in vitro. CTL lines specific for each peptide were established by stimulating peripheral blood mononuclear cells (PBMC) from an HLA-A2.1+ healthy donor with autologous dendritic cells loaded with TS peptide. Specific CTL lines showed HLA-A2.1-restricted cytotoxicity in vitro to HLA-A2.1+ target cells pulsed with the specific TS peptide and to HLA-class I matching colon carcinoma target cells over-expressing TS enzyme after exposure to 5-FU. Recognition by CTL lines suggests that these TS peptides may be potential candidates for use in a peptide-based vaccine against 5-FU resistant colon carcinoma.

Advanced breast cancer remains a major clinical problem. Current chemotherapy regimens are able to induce a clinical response in many patients but do not appear to influence significantly patients' survival. The use of new drugs such as mitoxantrone with a predicted lower toxicity and biochemical modulation of 5-fluorouracil with levo-folinate are extensively studied research areas that could combine good therapeutic efficacy with the maintenance of an acceptable quality of life. 34 patients with advanced breast carcinoma were included in the study. Only 4 women had received prior chemotherapy for advanced disease. Treatment plan was: 5-fluorouracil 400 mg/m2 + l-leucovorin 100 mg/m2 days 1-3, cyclophosphamide 600 mg/m2 and mitoxantrone 12-14 mg/m2 on day 3, q28. G-CSF (5 micrograms/kg/d days 7-14) was routinely delivered to the patients with the aim of maintaining dose intensity. 15 patients obtained a response for an overall response rate of 44%. Mean duration was 10.2+ and 11+ months for complete and partial responses respectively. Mean overall survival was 14.4+ months. A high complete response rate was seen in liver metastasis (44%), while lung lesions had a lower probability of response (25%). Toxicity was globally mild with 23% of grade 3 vomiting and 15% of grade 3-4 leukopenia. Two cases of cardiotoxicity were reported. No difference in response rate or toxicity was identified between patients receiving two different mitoxantrone doses (12 or 14 mg/m2). The schedule employed appears to be well tolerated and active in the treatment of advanced breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

We have studied the interaction of glutathione-depleting concentrations of buthionine sulfoximine (BSO) with the anti-proliferative activity of doxorubicin (DXR) in three tumor lines, the mouse B16 melanoma. Friend erythroleukemia and the human K562 leukemia, both as DXR-sensitive and-resistant (with typical multidrug resistance) variants. BSO significantly enhanced the DXR effects in the wild-type Friend and K562 leukemias, and especially in the drug-resistant subline of Friend leukemia. BSO did not modify DXR accumulation and retention in the latter clone. Moreover, neither BSO nor verapamil used alone completely reversed the resistance to DXR of this cell line; their combination was more efficient and increased its drug sensitivity to a level closer to that of the parental counterpart. These results seem to indicate that the status of glutathione and of the enzymes related to it contributes to the resistance of Friend leukemia to DXR. An interesting additional finding was that BSO significantly synergizes with the antiproliferative effects of vincristine in the drug-sensitive variants of Friend and K562 leukemias.

Twenty consecutive patients with advanced breast cancer were treated with a combination of cyclophosphamide 600 mg/m2 i.v. on day 1, epidoxorubicin 75 mg/m2 on day 1, and 5-fluorouracil 375 mg/m2 i.v. with folinic acid 200 mg/m2 i.v. on days 1----3. The overall response rate was 60%, with 10% of patients showing a complete response with a mean duration of 11.1 + months, and 50% of patients a partial response of 7.4 + months. A stabilization of 5.2 + months was obtained in 20% of cases, while 20% of patients progressed. The most frequently observed toxicity was leukopenia, while expected mucosal toxicities were rather mild.

A phase I study of 5-fluorouracil 600 mg/m2/week and folinic acid 500 mg/m2/week on day 1 and cisplatin administered weekly on day 2 was carried out on 30 patients with metastatic colorectal carcinoma of which 20 patients were pretreated with 5-fluorouracil. The first group of patients received cisplatin at the dose of 5 mg/m2/week. Cisplatin was then escalated to 10, 15, 20, 25, 30, and 35 mg/m2/week for subsequent groups of patients. Gastrointestinal side-effects were the dose-limiting toxicity. A therapy related death was seen at the dose of 35 mg/m2/week of cisplatin. The maximally tolerated dose of cisplatin in combination with 5-fluorouracil and citrovorum factor is 20 mg/m2/week. The optimally tolerated dose of 5-fluorouracil is 400 mg/m2/week in modulation with citrovorum factor 500 mg/m2/week. The recommended doses for a phase II study are cisplatin 20 mg/m2/week, 5-fluorouracil 400 mg/m2/week, and citrovorum factor 500 mg/m2/week.

A dose optimization study was carried out with the aim of identifying the maximally tolerated dose of recombinant alpha interferon-2a (raIFN-2a) in combination with 5-fluorouracil (5FU). 5FU was given at the dose of 750 mg/m2 over a 4-hour infusion on day 1- - greater than 5 followed by 750 mg/m2 weekly i.v. bolus. Recombinant aIFN-2a was started at 3 x 10(6) IU subcutaneously three times/week. 12 patients with advanced colorectal carcinoma were included in the study. 10 patients had previously received chemotherapy for advanced disease. Severe fatigue, most likely attributable to rIFN, was the dose-limiting toxicity. The dosage of raIFN-2a could not be further escalated above 12 x 10(6) IU. At this dose level all patients required dose reduction due to fatigue, fever, myalgia and severe reduction of performance status.

5-Fluorouracil (5-FU) has been the treatment of choice for colorectal carcinoma with an overall response rate of about 20%. Recent studies have shown that folate (LV) can increase 5-FU therapeutic efficacy, achieving about a 40% response rate without a clear impact on survival. Cisplatinum (CDDP) is usually inactive in colorectal carcinoma, but the association with 5-FU results in a synergistic antineoplastic effect. A phase I-II study was done to assess the maximally tolerated dose (MTD) of CDDP in association with 5-FU + LV. The MTD for CDDP was 20 mg/m2/wk in association with 5-FU 400-500 mg/m2/wk and LV 500 mg/m2/wk. WHO criteria were used for evaluation of both toxicity and response. In the phase I part we found that the main side-effect in 27 evaluable patients (pts) was gastrointestinal toxicity, mainly in the form of nausea/vomiting (92%) and diarrhea (70%) which caused one therapy-related death. Renal (26%) and marrow (59%) toxicity were acceptable. In the phase II part of the study 1 out of 19 evaluable pts (5%) had a complete response of 309 days, 3 pts achieved a partial response (16%) with a median duration od 410 days, 2 pts had a minimal response (10%) with a median duration of 261 days, and 8 pts experienced no change (42%) with a mean duration of 196 + days. In our opinion the 21% response rate obtained in this series is not satisfactory. Nevertheless the very high number of minimal response + no change patients together with the interesting impact on survival in responders may suggest further phase II-III studies.

Twenty-one patients with histologically proven advanced or disseminated non-small cell lung cancer were treated with cisplatinum 80 mg/m2 i.v. day 1 and etoposide (VP16) 80 mg/m2 i.v. day 1- greater than 3.15 patients were evaluable for response. One patient (6.6%) achieved a complete response, 4 (26.7%) a partial response and 6 (40.0%) a stabilization of disease. Four patients (26.7%) progressed. An improvement in performance status was obtained in more than 50% of cases. Responders had a mean survival of 345 + days, while non-responders 191.7 days. The treatment was generally well tolerated. In our opinion this combination regimen offers good palliation for patients affected by advanced and/or metastatic non-small cell lung cancer.

Twenty patients with histologically confirmed small-cell lung cancer were treated with cyclophosphamide 1000 mg/m2 i.v. on day 1, vincristine 1.4 mg/m2 i.v. day 1, and adriamycin 50 mg/m2 i.v. on day 1. This protocol was repeated every 21 days. Out of 17 evaluable patients 2 obtained a complete response (12%) with a mean duration of 11 months, 4 patients achieved a partial response with a mean duration of 6.3+ months, and 1 had a minimal response of 7.2 months. Two patients had a stabilization which lasted a mean of 4+ months, while 8 patients progressed. Although the mean survival was higher in responders than in non-responders, the difference in survival time was not statistically significant. The treatment was quite well tolerated with hematological toxicity in 78% of cases, oral and gastrointestinal toxicity in 83%, alopecia in 78%, and neurotoxicity in 16% of cases.