Pharmacokinetics of BW12C and mitomycin C,given in combination in a phase 1 study in patients with advanced gastrointestinal cancer

The effect of combining the oxygen-transport-modifying drug BW12C with mitomycin C was investigated in a phase 1 study of 26 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 60 mg/kg. Dose-limiting toxicity of vomiting was experienced at doses greater than 50 mg/kg. This corresponded to whole blood levels 700 g/ml and to >50% haemoglobin modification. Whole blood concentrations of BW12C and modification of the haemoglobin oxygen saturation curve were linearly dependent on dose. BW12C whole blood pharmacokinetics were best described by a one-compartment model and were clearly dose-dependent. The half-life increased from 2.1 h at a dose of 20 mg/kg to 7.2 h at a dose of 60 mg/kg. The AUC increased in a similar non-linear fashion with increasing dose. Mitomycin C was given at a fixed dose of 20 mg/m² at the end of the BW12C infusion. Mitomycin C plasma pharmacokinetics fitted a two-compartment model, giving a mean beta half-life of 50±7 min and AUC of 1.1±0.08 g/ml h, and were unaffected by the combined treatment. There was no evidence of increased mitomycin C toxicity.     

Pharmacokinetics of mitomycin C in humans

This paper describes an investigation into the pharmacokinetic behavior of mitomycin C (MMC) in 36 patients receiving either single-agent chemotherapy (10 to 20 mg/sq m), or a combination regimen including MMC (5 to 10 mg/sq m). A high-performance liquid chromatographic assay of MMC was applied for the analysis of plasma, urine, bile, and ascites fluid samples. The detection limit is 1 ng/ml sample. Most patients were given short-term i.v. infusion, although other methods of administration were used as well. Most plasma concentration-time curves fit a two-compartment model. Pharmacokinetic parameters revealed large interindividual variations. Median terminal half-lives in single-agent chemotherapy and combination chemotherapy were 50 and 42 min, respectively. The apparent volume of the central compartment was 7 liters/sq m in both groups. The volume of distribution was 22 liters/sq m in single-agent chemotherapy, and 25 litres/sq m in combination chemotherapy. Linear regression analysis of the area under the plasma concentration-time curve versus the dose did not produce any evidence that the pharmacokinetics was dose dependent. However, differences were observed between patients receiving MMC alone and those on combination chemotherapy, in particular with regard to the total body clearance: 18 liters/hr/sq m for single-agent chemotherapy and 28 liters/hr/sq m for combination chemotherapy. Urinary recovery was limited to a maximum of 15% of the administered dose. In one patient studied, MMC was found to be present in the bile. There is evidence for enterohepatic circulation of MMC, and MMC was also found to penetrate into the ascites fluid.     

Pharmacokinetics of mitomycin C in rabbit and human

Summary A sensitive and specific high-pressure liquid chromatographic assay was developed to characterize the plasma elimination and urinary excretion of mitomycin C in humans. Extraction of mitomycin C and an internal standard, porfiromycin, from plasma by chromatography over a non-ionic resin, Porapak Q, yields high recovery of both compounds and facilitates measurement of as little as 5 ng mitomycin C by reversed-phase high-pressure liquid chromatography. The assay was used to characterize the plasma elimination of mitomycin C in rabbits and was shown to be applicable to the characterization of the pharmacokinetics of mitomycin C in humans receiving as little as 8 mg/m².     

Pharmacokinetics of mitomycin C after resection of peritoneal carcinomatosis and intraperitoneal chemohyperthermic perfusion

Over the last few years surgery on patients with abdominal malignancies has become more aggressive but the majority of patients present locoregional recurrence as peritoneal dissemination. Cytoreductive surgery followed by intraperitoneal chemohyperthermic perfusion (ICHP) has been described for treatment and prevention of locoregional cancer spread from various origins. This paper reports our study of the pharmacokinetics of mitomycin C (MMC) administered by intraperitoneal chemohyperthermic perfusion (ICHP) in patients with peritoneal carcinomatosis. 28 patients received MMC 20 mg/m2 intraperitoneally as a perfusion over 60 min. MMC was determined in perfusate, plasma and urine samples with a UV-HPLC method. A compartmental model was used to fit the drug concentrations in plasma and perfusate. Our results showed a mean maximum plasma concentration (Cmax) of 0.14 +/- 0.086 microg/ml with a peak time (Tmax) of 48..7 +/- 5.61 min. The mean area under the curve (AUC) and terminal half-life (t1/2) were 15.8 +/- 9.8 mg x min/L and 83.7 +/- 31.74 min respectively. Clearance (CL) was estimated by fitting the data by a compartmental model and the mean value was 72 +/- 66 L/h. The percent of the dose absorbed was very variable and ranged between 14 and 57% (mean 37 +/- 14%). The mean percentage of dose recovered unchanged in the urine during 24 hours was 7.21 +/- 3.73%. We conclude that ICHP in patients with peritoneal surface malignancies seems to have clinical value since it gives high peritoneal and tumor MMC concentrations with limited systemic exposure and toxicity.     

Effects of mitomycin C alone and in combination with X-rays on EMT6 mouse mammary tumors in vivo

The effects of mitomycin C alone and in combination with radiation on the cells of EMT6 mouse mammary tumors in BALB/cKaRw mice were examined. At doses near the toxic level, approximately 98% of the tumor cells were killed by a single injection of mitomycin C. Both proliferating and quiescent cells and both hypoxic and aerobic cells were killed by the drug. Cytotoxicity with mitomycin C occurred rapidly and was apparently complete within 30 minutes after injection of the drug . No evidence was found for repair of potentially lethal mitomycin C damage or sublethal mitomycin C damage by the tumor cells. Mitomycin C and radiation in combination produced an additive cytotoxicity; neither agent was found to alter significantly the shape of the dose-response curve for the other agent. The cytotoxicity of mitomycin C and radiation in combination depended on the sequence and timing of the treatments; additive toxicities were obtained when mitomycin C was given just after, just before, or up to 24 hours before irradiation, but the combination was less effective when mitomycin C was given 2-12 hours after irradiation.     

A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma.

BACKGROUND. In an effort to confirm the efficacy of mitomycin C against metastatic squamous cell lung carcinoma and to compare the efficacy of single-agent therapy with a combination containing cisplatin, the authors conducted a randomized Phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin (MVP). METHODS. All patients had advanced squamous cell lung carcinoma, and survival was the primary end point. There were 133 eligible patients who received either mitomycin C alone (n = 64) or MVP (n = 69). The two groups were similar with respect to performance score, disease status, age, sex, and stage. RESULTS. The major objective response rates were 30% (95% confidence interval [CI], 18-41%) and 43% (95% CI, 32-55%) for mitomycin C alone and MVP, respectively (P = 0.1). The median time to progression was 83 days for mitomycin C alone, compared with 119 days for MVP (P = 0.026). The median survival time was 114 days for mitomycin C and 163 days for MVP (P = 0.09). The 1-year survival rates were equivalent. Myelosuppression was the major toxicity, and there were significantly greater leukocyte nadirs with MVP therapy (P < 0.001). CONCLUSION. Mitomycin C has antitumor activity against squamous cell lung carcinoma when used alone or in combination with MVP. The regimen containing cisplatin had marginally increased activity that did not translate into a clinically significant survival advantage.     

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)     

Thymidine as an anticancer agent,alone or in combination

Summary The value of thymidine as a cytotoxic drug alone or in combination with other pyrimidine antimetabolites has received considerable attention in recent years.In this paper, the biochemical basis for the cytotoxicity of thymidine and its interaction with other pyrimidine antimetabolites is described. It is indicated that early clinical trials have largely failed to substantiate data from experimental studies that have shown thymidine to be an effective antimetabolite and capable of potentiating the antineoplastic effect of several other agents.It is suggested that tumours likely to respond to thymidine alone or in combination may be identified by measuring in clinical tumour specimens known biochemical determinats of thymidine efficacy.PHE is an Applied Health Fellow of the National Health and Medical Research Council of Australia     

Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer

A randomized clinical trial was performed to determine if combination therapy with doxorubicin, vincristine, and mitomycin C (DVM) was superior to doxorubicin alone in women with metastatic breast cancer for whom prior chemotherapy had failed. A total of 185 women were randomized to monthly courses of D (60 mg/m2, observation after 500 mg/m2); or D (50 mg/m2, maximum cumulative dose 500 mg/m2), V (1 mg/m2), and M (10 mg/m2, given every other cycle). Patients failing after D alone could receive V (1 mg weekly for 5 weeks, then 1.2 mg/m2 every 5 weeks) plus M (12 mg/m2 every 5 weeks). Objective responses were seen in 24 of 95 patients (25%) on D alone and 39 of 90 patients (43%) on DVM (two-sided p = 0.01). The time to disease progression distribution was significantly better for DVM (two-sided p = 0.02), but the magnitude of the advantage was small with the medians being 2.7 months for D and 4.2 months for DVM. There was no significant difference in survival between the two regimens. The degree of leukopenia was greater for DVM both in terms of median white blood cell nadir (1,300/microL versus 1,700/microL) and percentage of patients with a nadir less than 1,000/microL (33% versus 16%). A total of 45 patients received VM following D alone, and only seven (16%) achieved an objective response. We conclude that, despite a significantly higher response rate and longer time to progression, the degree of clinical benefit is not sufficient to recommend the combination of DVM over D alone as second-line therapy for women with metastatic breast cancer. The level of efficacy seen with VM as tertiary therapy is low and is of such a magnitude to suggest that V adds little but toxicity to M.     

Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer

Randomised studies in locally advanced cervical cancer patients showed that cisplatin should be given concurrently with radiotherapy, because of a better long-term survival compared to radiotherapy alone. This increases the relevance of treatment related toxicity. This review summarises the acute and long-term toxicity of radiotherapy given with or without chemotherapy for cervical cancer. Acute toxicity (all grades) of radiotherapy is reported in 61% of the patients in the rectosigmoid, in 27% as urological, in 27% as skin and in 20% as gynaecological toxicity. Moderate and severe morbidity consists of 5% to 7% gastrointestinal and 1% to 4% genitourinary toxicity. Adding chemotherapy to radiotherapy increases acute haematological toxicity to 5% to 37% of the patients and nausea and vomiting in 12% to 14%. Late effects of radiotherapy include gastrointestinal, urological, female reproductive tract, skeletal and vascular toxicity, secondary malignancies and quality of life issues. For at least 20 years after treatment, new side effects may develop. Gastrointestinal toxicity usually occurs in the first 2 years after treatment in about 10% of the patients. The incidence of moderate and severe urological toxicity can increase up to 10% and rises over time. Gynaecological toxicity usually occurs shortly after treatment while skeletal and vascular toxicity can occur years to decades later. Thus far, no increase in late toxicity has been observed after the addition of cisplatin to radiotherapy. Finally, methods to prevent or decrease late toxicity and therapeutical options are discussed. However, most randomised studies still have a limited follow-up period.     

Pharmacokinetics of mitomycin C in non-oat cell carcinoma of the lung

Summary The disposition kinetics of the cancer chemotherapeutic agent mitomycin C have been studied in six male patients receiving mitomycin C in combination with cisplatin and vinblastine for non-oat cell carcinoma of the lung. Following rapid IV administration of mitomycin C (10 mg/m²), serum concentration-time course data were biexponential, with biologic half-lives of 46.2 ± 12.1 min (mean ± SD). Pharmacokinetic analysis of data by the CSTRIP and NONLIN digital computer programs generated parameters which suggested extensive distribution (V_area=656.8±169.8 ml·kg^–1, mean ±SD) and, as reported for other alkylating agents, rapid elimination (total body clearance=10.3 ± 3.2 ml · kg^–1 · min^–1, mean ± SD). Interpatient variations in pharmacokinetic parameters were relatively small, suggesting that close monitoring of mitomycin C therapy might be unnecessary in patients with normal renal and hepatic function.     

Redox-dependent toxicity of diepoxybutane and mitomycin C in sea urchin embryogenesis

The effects and mechanisms of action of diepoxybutane (DEB) and mitomycin C (MMC) were investigated on sea urchin embryogenesis, (Sphaerechinus granularis and Paracentrotus lividus). DEB- and MMC-induced toxicity was evaluated by means of selected end-points, including developmental defects, cytogenetic abnormalities and alterations in the redox status [oxygen-dependent toxicity, Mn-superoxide dismutase (MnSOD) and catalase activities and glutathione (GSH) levels]. Both DEB and MMC exhibited developmental toxicity (at concentrations ranging from 3 x 10(-5) to 3 x 10(-4) M and 3 x 10(-6) to 3 x 10(-5) M, respectively) expressed as larval abnormalities, developmental arrest and mortality. The developmental effects of both compounds were significantly affected by oxygen at levels ranging from 5 to 40%. These results confirmed previous evidence for oxygen-dependent MMC toxicity and are the first report of oxygen dependence for DEB toxicity. Both DEB and MMC exerted significant cytogenetic abnormalities, including mitotoxicity and mitotic aberrations, but with different trends between the two chemicals, at the same concentrations as exerted developmental toxicity. The formation of reactive oxygen species was evaluated using: (i) luminol-dependent chemiluminescence (LDCL); (ii) reactions of the main antioxidant systems, such as GSH content and MnSOD and catalase activities. The results point to clear-cut differences in the effects induced by DEB and MMC. Thus, DEB suppressed GSH content within the concentration range 10(-7)-3 x 10(-5) M. The activity of catalase was stimulated at lower DEB levels (10(-7)-10(-6) M) and then decreased at higher DEB concentrations (> or =10(-5) M). Increasing MMC concentrations induced LDCL and MnSOD activity (> or =10(-6) M) greatly and modulated catalase activity (10(-7) - 10(-6) M). GSH levels were unaffected by MMC. The results suggest that oxidative stress contributes to the developmental and genotoxic effects of both toxins studied, although through different mechanisms.     

Nilotinib alone or in combination with selumetinib is a drug candidate for neurofibromatosis type 2

Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) leading to strong, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec(;) Novartis) and nilotinib (Tasigna(;) Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-β and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors.     

Effects of 5,8-dideazaisopteroylglutamate (IAHQ) on L1210 leukemia in mice when given alone and in combination with methotrexate,probenecid, or verapamil

Summary The folate analogue 5,8-dideazaisopteroylglutamate (IAHQ; NSC-289517) inhibits the growth of a variety of human tumor cells in vitro such as colon, breast and osteosarcoma. Since IAHQ has only modest activity against L1210 leukemia in mice, it was tested in combination with methotrexate (MTX), probenecid, or verapamil in an effort to enhance efficacy. Single drug or drug combinations were administered every other day 3 or 5 times beginning on day 1 following the administration of 10⁶ L1210 cells per animal. The combination of IAHQ (100 mg/kg) plus MTX (10 mg/kg) produced a decrease in mean survival time compared to that of MTX alone, regardless of whether the drugs were initiated on the same day or whether either one was started 2 days prior to the other. IAHQ (150 mg/kg) plus verapamil (5, 10, or 20 mg/kg) did not alter significantly the results produced by IAHQ alone. However, the combination of IAHQ (150 mg/kg) plus probenecid (250 mg/kg) augmented the increase in mean survival time above that produced by IAHQ alone by 82% (p=>0.001). The results suggest that probenecid could be used to enhance the effectiveness of IAHQ against solid tumors such as colon adenocarcinoma.Supported by Public Health Service Grant CA-25014 (National Cancer Institute) from the National Institutes of Health, Department of Health and Human Services, by the Veterans Administration, and by VA-NCI Interagency Agreement IGA V101 (134A) P-77014. Presented in part at the Annual Meeting of the Southeastern Section, Society for Experimental Biology and Medicine, Charleston, SC, November 14–15, 1985.     

Renal damage in mice after treatment with cisplatinum alone or in combination with X-irradiation

Functional kidney damage in mice was measured (using clearance of 51Cr-EDTA) from 1 to 39 weeks after treatment with single doses of cisplatinum (c-DDP), X rays, or their combination. After c-DDP alone renal damage was observed within 1 week. From 1 to 7 weeks there was recovery of function after low drug doses but after doses in excess of 6 mg/kg some damage persisted. After irradiation alone there was no measurable change in function for 20 weeks. Beyond this time there was a dose dependent and progressive deterioration of function. c-DDP given before or after irradiation caused more damage than either agent alone. During the first 20 weeks independent toxicities accounted for most of this effect but at later times modification of radiation damage possibly contributed. The greatest enhancements were observed when c-DDP was given 1/2 hour before to 1 day after irradiation (Dose Modifying Factor, DMF, 1.3). c-DDP given 3 to 4 weeks before X rays caused only a slight enhancement of damage (DMF 1.1).     

Hematologic toxicity of cisplatin and mitomycin in combination for squamous cell carcinoma of esophagus

Seventy-six patients with squamous cell carcinoma of the esophagus (SCE) were treated with either cisplatin and mitomycin in combination or as single agents on ECOG protocol 2278. Sixty-six patients were evaluated for toxicity. Of 13 evaluable mitomycin and cisplatin treated patients, six (46%) experienced ECOG grade 4 thrombocytopenia and/or leukopenia. Of 28 evaluable patients treated with mitomycin alone, two (7%) experienced such toxicity; and of 25 evaluable patients treated with cisplatin alone, none experienced this toxicity. The average total dose prior to toxicity for those receiving mitomycin and cisplatin in combination was 51 mg and 131 mg, respectively, with average time to toxicity 3.6 weeks. For those two patients who received mitomycin alone, the average total dose was 68 mg and average time to toxicity 6.5 weeks. For those patients receiving cisplatin alone, the average total dose was 220 mg. The reasons for the enhanced hematologic toxicity of the agents together are not apparent, but it would be prudent to caution investigators using these agents in combination with potentially myelosuppressive drugs.     

Mitomycin C toxicity and pharmacokinetics in mice given sulfur nucleophiles

The sulfur nucleophiles, sodium thiosulfate (Na2S2O3) and N-acetylcysteine (NAC) given in maximally tolerated doses did not reduce the hematologic toxicity of high dose mitomycin C (MMC) in normal mice. In addition, neither sulfur nucleophile significantly altered the antileukemic activity of MMC. Pharmacokinetic studies of MMC in normal mice, demonstrated rapid plasma elimination (T1/2 beta = 0.53 hrs) and substantial drug distribution to the bone marrow which was enhanced by NAC. These results demonstrate a lack of MMC antidotal activity for Na2S2O3 and NAC.     

Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C

One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy.     

A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer.

BACKGROUND: A phase III single-center randomized trial was performed in order to determine whether the addition of mitomycin C (MMC) and/or doxorubicin to 5-fluorouracil (5-FU) as adjuvant chemotherapy could influence survival in patients with curatively resected gastric cancer. PATIENTS AND METHODS: A total of 416 patients who had undergone curative resection for stage IB-IIIB gastric adenocarcinoma were stratified according to the stage and type of surgery, and then randomized to receive one of the three chemotherapy regimens, 5-FU alone (F) or 5-FU and MMC (FM) or 5-FU, doxorubicin and MMC (FAM) within 5 weeks after surgery. RESULTS: Of 416 patients registered, 395 (133 in F, 131 in FM and 131 in FAM) were assessable. Median follow-up duration was 91 months. Five-year overall survival rates were 67.2% for F, 67.0% for FM and 66.7% for FAM (P = 0.97). Five-year disease-free survival rates were 62.1% for F, 63.3% for FM and 62.5% for FAM (P = 0.83). Hematological toxicities were more frequent in the FM and FAM groups, whereas stomatitis was more common in the F group. CONCLUSIONS: Compared with adjuvant 5-FU alone, the addition of MMC and/or doxorubicin to 5-FU did not influence survival in patients with resected gastric cancer.