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5-Fluorouracil, doxorubicin and mitomycin C (FAM) combination chemotherapy for metastatic adenocarcinoma of unknown primary.

The prognosis of patients with adenocarcinoma of unknown primary (ACUP) is dismal. Various chemotherapy regimens have yielded disappointing response rates and survival. Based on a promising report of Goldberg et al. (J Clin Oncol 1986, 4, 395-399) we performed a phase II study with 5-fluorouracil, adriamycin and mitomycin C (FAM). Only three out of 22 evaluable patients achieved a partial response (14%) for a duration of 22, 30 and 74+ weeks. Median survival was 54+ weeks (range 35-74+ weeks) for responding patients and 33+ weeks (range 9-74+ weeks) for all treated patients. One patient (5%) developed mitomycin C induced hemolytic uremic syndrome. FAM cannot be recommended for routine use in patients with ACUP.

Adenocarcinoma↗

Bladder epithelial hyperplasia in F344 rats after intravesical instillation of the antitumor chemotherapeutic agents Adriamycin and mitomycin C.

The effects of intravesical instillation of the antineoplastic antibiotics, Adriamycin or mitomycin C, on the urinary bladder epithelium of female F344 rats were evaluated using a combined immunohistochemical and morphological approach. Four weeks treatment with Adriamycin or mitomycin C induced an increase of DNA synthesis and was associated with simple hyperplasia characterized by elevated nuclear cytoplasmic ratios, cytomegaly and pleomorphism. Under the scanning electron microscope (SEM), luminal cell surface alterations such as pleomorphic microvilli were observed. Severity of the lesions was greatest in the Adriamycin group and although treatment of the saline vehicle alone also brought about development of simple hyperplasia, this was very slight and not accompanied by cellular pleomorphism. The present results demonstrated that intravesical instillation of antineoplastic agents can cause a proliferative response and cytotoxicity after only short-term treatment and suggest that this chemotherapy could itself play a possible role in promotion of bladder carcinogenesis or cancer development.

Administration, Intravesical↗

Free-radical formation by mitomycin C and its novel analogs in cardiac microsomes and the perfused rat heart.

Using a spin-trapping technique, we have examined free-radical formation by mitomycin C and its analogs, BMY 25282 and BMY 25067, in rat cardiac microsomes and isolated perfused rat hearts. All three drugs stimulated 2--4-fold OH radical formation in cardiac microsomes which was inhibited by SOD and catalase. Superoxide anion radical was also detected in the presence of diethylenetetraaminopentaacetic acid. Addition of DMSO yielded methyl radicals, thus indicating the production of free OH under these conditions. Similar stimulation of OH formation (2--3-fold) in the perfusates from rat hearts was detected with all three drugs. Perfusion with catalase (550 U/ml) completely suppressed the OH signal both in the presence and absence of the drugs, thus suggesting the intermediacy of hydrogen peroxide. However, BMY 25067-induced OH formation was more sensitive to inhibition by superoxide dismutase (SOD) and the iron chelator ICRF-187. Perfusion with DMSO produced methyl radicals at the expense of OH in the presence of all three drugs. SOD and catalase inhibited DMPO-OH signals, indicating that most of the OH formation was extracellular in this setting. While mitomycin C and BMY 25067 (up to 10 microM) did not affect the heart rate, perfusion with 10 microM BMY 25282 caused acute arrhythmia and cardiac standstill within 20 min. An initial surge in OH formation (2-fold) accompanied this cardiotoxic effect. Both the arrhythmia and the free radical signal were partially blocked by SOD, catalase and ICRF-187, indicating that iron-dependent oxygen radical formation from BMY-25282 (and possibly other compounds) is involved, in part, in inducing toxic manifestations in the rat heart and possibly in clinic.

Animals↗

Second generation analogs of etoposide and mitomycin C.

Programs directed towards the selection of etoposide and mitomycin C analogs which exhibit superior activity, reduced toxicity and improved pharmaceutics have met with partial success. Etopofos (BMY 40481) has been chosen for development as a prodrug of etoposide possessing superior pharmaceutical properties. BMY 25067, an analog of mitomycin C, is also under development based on its improved activity profile, acceptable toxicology profile and possibly different mechanism of action.

Animals↗

Combination therapy with misonidazole and mitomycin C: lack of chemosensitization of EMT6 tumor cells in vivo or in vitro.

The effect of the nitroimidazole misonidazole on the cytotoxicity of mitomycin C was examined using EMT6 Rw tumors in mice and EMT6 cells in culture. In contrast to reports by others using a different tumor system, we were unable to detect any significant increase of mitomycin cytotoxicity by misonidazole in vivo using tumor cell survival or host toxicity endpoints. Studies with cells in vitro provided no evidence for marked chemosensitization of either hypoxic or aerobic cells.

Animals↗

Concomitant 5-fluorouracil, mitomycin-C, and radiotherapy for advanced gynecologic malignancies.

Advanced gynecologic neoplasms continue to pose major therapeutic problems; 22,500 deaths were estimated for 1987. Between December 1983 and October 1985, there were 25 patients evaluated at our institution who on joint evaluation by the radiation oncologist and gynecologic oncologists were found to have extensive disease not amenable to standard therapy. Patients were to be treated by a combined modality approach with Mitomycin-C and 5-Fluorouracil given concomitantly with radiotherapy. Nineteen patients were treated definitively and six patients were treated with palliative intent (24 primary, 1 recurrent). The patients ranged in age from 27 to 90 years with a mean of 57.3 and a median of 57. Primary sites at presentation were: cervix--14 patients, vagina--7 patients, and vulva--4 patients. The initial FIGO stages at time of the initial diagnosis were: Stage I--1 (recurrent), Stage II--4, Stage III--15, and Stage IV--5. Chemotherapy consisted of 5-fluorouracil 1 gm/m2 given continuous infusion for 4 days with Mitomycin-C 10 mg/m2 IV push on day 1. Radiation therapy was started on day 1. Only 2 of 25 patients (8%) required chemotherapy reductions. All 25 patients received mega-voltage irradiation. The external beam dose range was 2000-6500 cGy and 14/25 patients received intracavitary or interstitial therapy. In the definitive patient group, there was no reduction in the therapeutic dose. Only four patients underwent surgical therapy. With a minimum follow-up of 8 months and a median follow-up of 28 months, the survival for the entire population was 56%. Fourteen of the 19 patients (74%) treated definitively are surviving with 12 patients having no evidence of disease. Survival by site in the definitive therapy group was cervix--70%, vulva--100%, and vagina--66%. The overall response rate was 84% at 3 and 9 months (3 months; CR--36%, PR--48%, and 9 months; CR--60%, PR--24%). There were no local recurrences in the 12 patients who achieved a complete response. Three patients died of metastatic disease alone and the overall local control was 60%. Evaluation of therapeutic side effects was performed. Hematologic analysis by the Southeastern Oncology Group criteria showed neutropenia in 14 patients (1--life-threatening, 2--severe, and 11 patients--mild/moderate) and thrombocytopenia was observed in 11 patients (all mild or moderate). All hematologic complications resolved. Acute complications did not appear increased except for the addition of mild oral mucositis (12 patients). Six patients demonstrated late effects with only 2 patients felt to have severe complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Concomitant 5-fluorouracil infusion, mitomycin C and radical radiation therapy in esophageal squamous cell carcinoma.

This is a retrospective comparison of patients with unresected esophageal squamous cell carcinoma treated by radiation therapy and chemotherapy (21 patients) versus radiation therapy alone (34 patients). Pretreatment characteristics were comparable in both groups. In the combined modality group, treatment was given in split courses with concomitant radiation therapy (20 to 25 Gy in 10 fractions on days 1-12 and days 42-54) and chemotherapy (bolus Mitomycin C on day 1; 96 hr. of continuous 5 Fluorouracil infusion on days 1-4 and days 42-46). There was improvement in local disease control with the combined modality approach. Initial complete response was achieved in 86% of the radiation and chemotherapy group, versus 57% of the radiation alone group. The one-year local relapse-free rate was 67% versus 35%, and 2 year rate was 41% versus 28%. (p less than 0.05). The 1-year and 2-year survival was 64% and 32% respectively, for the radiation and chemotherapy group, versus 28% and 10% respectively for the radiation alone group (p less than 0.05). The majority of patients had disease relapsed, 81% of the combined modality group and 97% of the radiation alone group. However, the pattern of failure was different in the two groups. In the radiation and chemotherapy group, 29% had local failure alone, 53% had distant failure alone, and 18% had both local and distant failure. In the radiation alone group, 33% had local failure alone, 24% had distant failure alone, and 43% had both local and distant failure. Concomitant radiation therapy, 5 Fluorouracil infusion and bolus Mitomycin C is effective treatment for local control in esophageal squamous cell carcinoma, but not for distant hematogenous metastases. This combined modality treatment was well tolerated, with little additional hematological toxicity, esophagitis and stomatitis over radiation therapy alone.

Aged↗

Comparative evaluation of three tests for the detection of Escherichia coli cytotoxic necrotizing factors (CNF1 and CNF2) using filtrates of cultures treated with mitomycin C.

Necrotizing Escherichia coli (NTEC) strains grown in the presence of mitomycin C released cell associated necrotizing factors CNF1 and CNF2 to culture medium. Using culture filtrates from 96 mitomycin C treated E. coli strains, we have found that a modified HeLa cell assay was a more sensitive and specific method for the detection of CNF1 and CNF2 than the Vero cell assay and the rabbit skin test.

Animals↗

Automated analysis of mitomycin C in body fluids by high-performance liquid chromatography with on-line sample pre-treatment.

A fully automated liquid chromatographic system for the bioanalysis of mitomycin C has been described. The isolation of the analyte from the biological matrix (plasma, ascites and urine) is performed using a continuous-flow system equipped with a dialysis membrane in order to remove proteins. The samples are concentrated on a reversed-phase pre-column and subsequently introduced on to a reversed-phase analytical column by applying column-switching techniques. The drug is detected by absorbance measurements at 360 nm. Using the described system up to 100 samples a day can be analysed with determination limits of the order of 1 ng/ml, with a linear dynamic range of at least three decades for plasma and urine samples. The procedure was applied to pharmacokinetic studies of ovarian cancer patients treated intraperitoneally with mitomycin C.

Ascitic Fluid↗

Liquid chromatography-thermospray mass spectrometry of DNA adducts formed with mitomycin C, porfiromycin and thiotepa.

High-performance liquid chromatography (HPLC) and thermospray mass spectrometry were combined for the analysis of DNA adducts formed from the interaction of the anticancer drugs mitomycin C, porfiromycin and thiotepa with calf thymus DNA. The adducts formed from reaction of mitomycin C and porfiromycin with DNA were separated from unmodified nucleosides by HPLC on a C18 column and identified by thermospray mass spectrometry. Thiotepa DNA adducts readily depurinated from DNA and were chromatographed and identified by thermospray liquid chromatography-mass spectrometry as the modified bases without the ribose moiety attached. The utility of thermospray mass spectrometry for the identification of microgram quantities of nucleoside adducts and depurinated base adducts of these anticancer drugs was demonstrated.

Animals↗

Topical mitomycin C therapy for carcinoma in situ of the bladder: a followup.

We studied 15 patients with histologically proved multifocal carcinoma in situ of the bladder who were in remission at a mean followup of 21 months after induction intravesical chemotherapy with mitomycin C. These patients have been followed for a further 28 months, for a total mean duration of 49 months. Of the 15 patients 4 suffered new areas of carcinoma in situ, including 3 who subsequently required cystectomy (2 after unsuccessful intravesical bacillus Calmette-Guerin therapy and 1 with a simultaneous invasive tumor). One patient underwent transurethral resection of the prostate for carcinoma in situ of the prostatic urethra, which subsequently was shown to be limited to mucosa and not involving the deeper ducts nor the stroma. Of the remaining 11 patients 1 died of unrelated disease and 2 suffered recurrent papillary transitional cell carcinoma treated successfully with a combination of intravesical bacillus Calmette-Guerin therapy and resection. The other 8 patients have remained free of tumor. None of the 15 patients had metastatic cancer. We believe that these results support the durability of response after induction mitomycin C therapy. We stress the necessity for prolonged close followup to detect recurrent tumor and to avoid metastatic disease.

Administration, Intravesical↗

Intravesical combination chemotherapy with mitomycin C and doxorubicin for carcinoma in situ of the bladder.

We treated 30 patients with carcinoma in situ of the bladder via intravesical combination chemotherapy. As an induction therapy 20 mg. mitomycin C on day 1 and 40 mg. doxorubicin on day 2 were instilled into the bladder once a week for 5 consecutive weeks. Patients who achieved complete response were assigned a maintenance instillation of mitomycin C alone every 2 to 4 weeks for 1 year. A total of 19 patients achieved complete response following an initial course of induction therapy and 2 partial responders to initial therapy also achieved complete response after repeated induction therapy, resulting in a 70 per cent over-all complete response rate. Toxicity was considerable with moderate to severe bladder irritation occurring in 20 patients but it was tolerable in the majority. Of 21 complete responses 13 remained free of disease for 6 to 43 months (average of 23 months), 5 had recurrent carcinoma in situ and 1 had invasive urethral cancer. In contrast, of 9 nonresponders 2 and 1 had invasive cancer of the bladder and ureter, respectively.

Administration, Intravesical↗

Treatment of urothelial carcinoma of the upper urinary tract following prostatocystectomy with mitomycin C instillation in the ileal loop.

We report a case of urothelial carcinoma of the upper urinary tract, which developed after prostatocystectomy. The patient was treated with instillations of 40 mg. mitomycin C in 40 ml. saline. No significant systemic side effects owing to perfusion of mitomycin C could be demonstrated. Complete remission of the small urothelial tumors occurred, as well as slight progression of a large pelvic carcinoma of the left kidney.

Aged↗

Treatment of superficial bladder cancer with intravesical mitomycin C: analysis of immediate and long-term response in 70 patients.

A total of 70 patients received intravesical mitomycin C for treatment of superficial bladder cancer. The drug was instilled weekly for 8 weeks. Thirty-nine patients (56 per cent) had failed thiotepa therapy and 25 had high grade tumors. Of the patients 27 (39 per cent) had complete eradication of tumor at the initial 3-month evaluation and an additional 27 had a partial response. The response did not vary with initial tumor grade or stage. Followup averaged 28 months for the 70 patients. A muscle invasive tumor developed during followup in 7 per cent of the patients with an initial complete response, 15 per cent with a partial response and 25 per cent of the initial failures. To date 5 patients (7 per cent) have died of bladder cancer. Intravesical mitomycin C is an effective modality for treatment of superficial bladder cancer. Patients achieving a complete response are at little risk for progressive disease.

Aged↗

Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma: influence on recurrence, progression and survival.

In a prospective controlled study the influence of long-term mitomycin C instillation therapy on tumor recurrence, progression and patient survival after transurethral resection of superficial bladder tumors was evaluated. This report is an update of a randomized controlled study that was stopped 1.5 years ago. The results show that long-term mitomycin C instillation therapy improves recurrence rate, progression rate and survival in patients with superficial bladder cancer.

Aged↗

Side effects associated with intravesical mitomycin.

The nature and severity of side effects accompanying intravesical chemotherapy with mitomycin C were studied in 29 patients. No patient experienced systemic toxicity. Local side effects developed in 7 patients (24 per cent), and consisted of moderate cystitis in 3 and drug-related palmar desquamation, with or without generalized rash, in 4. Based on skin tests 3 of these patients were believed to have a contact dermatitis. The fourth patient had a generalized rash, in addition to palmar desquamation, that appeared after subsequent instillations of mitomycin C and the drug had to be discontinued. Careful cleansing of the hands and perineum on the day of treatment can prevent most skin reactions.

Aged↗

Hepatic veno-occlusive disease after high-dose mitomycin C and autologous bone marrow transplantation therapy.

Three cases of veno-occlusive disease of the liver were diagnosed in four autopsied patients who had received high-dose mitomycin C therapy followed by autologous bone marrow transplantation, and the pathologic finding are reported. Review of 27 liver, examined post mortem, of patients receiving other high-dose chemotherapeutic regimens, 15 of them with subsequent autologous bone marrow transplantation, revealed no evidence of veno-occlusive disease. Veno-occlusive disease may now become a dose-limiting factor in the use of the combined high-dose mitomycin C-bone marrow transplantation therapy. Attention is also drawn to the increasing number of veno-occlusive disease cases being reported in associated with alkylating agents.

Adult↗

Wilms' tumour: association with cellular sensitivity to mitomycin C in patients and first-degree relatives.

To investigate whether predisposition to Wilms' tumour is associated with a particular defect in the handling of DNA damage, cell-lines from families in which the tumour had occurred were tested for sensitivity to a variety of DNA-damaging agents. Lymphoblastoid lines from both Wilms' tumour patients and their first-degree relatives showed increased sensitivity to the cross-linking agent, mitomycin C, but normal sensitivity to ultraviolet (UV) and gamma irradiation. Thus sensitivity to mitomycin C damage can be associated with the Wilms'-tumour-susceptible genotype and could be a genetic factor responsible for the modification of expression of this genotype.

Adult↗