Mg Of 5-fluorouracil Research Articles

Analysis of the results of combined therapy for maxillary carcinoma.

Maxillary sinus carcinomas usually are locally advanced. A wide variety of modalities, including surgery, radiation therapy, and intraarterial chemotherapy, alone or in combination, have been used. However, there is still much controversy with regard to the optimum treatment. From 1972 to 1986, 108 patients with squamous cell carcinoma of the maxillary sinus were treated at the Department of Radiology, University of Tokyo Hospital. From 1972 to 1974 (the first period), the treatment consisted of operation for reduction of tumor volume, daily cleaning of the maxillary antrum, 20 Gy of postoperative radiation therapy, and intraarterial infusion of 1500 mg of 5-fluorouracil (5-FU) and 3000 mg of 5-bromodeoxyuridine (BUdR). From 1975 to 1979 (the second period), the radiation dose was reduced to 10 Gy, and intraarterial infusion of 5-FU and BUdR was not performed. Surgery for reduction of tumor volume and daily cleaning of the antrum played a major role in this period. From 1980 to 1982 (the third period), daily cleaning of the antrum was not performed. Instead, the dose of radiation was increased to 50-60 Gy. From 1983 to 1986 (the fourth period), more extensive surgery to resect the tumor en bloc was introduced. The radiation dose was increased to 70 Gy. Intraarterial infusion of 3750 mg of 5-FU and 120 mg of cisplatin also was administered. The 5-year survival rate was 46% in the first period, 24% in the second period, 7.2% in the third period, and 53% in the fourth period. In the third period, there were more cases in which death resulted from a cause other than local failure, such as distant metastasis, pneumonia, or secondary primary cancer. Since 1984, we planned treatment with computed tomography (CT) and used the linear accelerator with a multileaf collimator to treat patients with an irregular field of irradiation. These have made it possible to administer radiation therapy in doses as high as 70 Gy without severe complications and improve the survival rate, especially for T4 disease. Radiation plays an important role in sterilizing malignant cells that cannot be removed by operation. The dose of radiation should be determined according to the volume of residual tumor. Careful treatment planning is required to irradiate the tumor adequately and reduce complications.

Molteno Implants-Reply

In Reply. —Dr Ortiz is to be commended on his accurate observation regarding both the use of fluorouracil and the 21-gauge needle in our article. 1 We did in fact administer 5 mg of fluorouracil over 14 days and not 0.5 to 1 mg as reported in the article. We used a 22-gauge needle to enter the anterior chamber. We apologize for overlooking these two errors in our proofreading of the article and thank Dr Ortiz for pointing them out.

Remission of Anterior Uveitis by Subconjunctival Fluorouracil

To the Editor. —Subconjunctival fluorouracil has been successfully used following filtering surgery for glaucoma secondary to uveitis 1,2 by preventing filtering bleb scarring through the inhibition of fibroblast proliferation. Based on the known beneficial effect of systemic cytotoxic drugs on certain types of uveitis, we decided, following such filtering surgery, to treat anterior uveitis with fluorouracil simultaneously with its use in the prevention of bleb scarring. Report of Cases. —Three patients (Table) experienced chronic, unilateral, mild (1+ cell and flare) to severe (3+ cell and flare) anterior uveitis. All three were being treated with local and systemic steroids. Due to uncontrolled glaucoma, filtering surgery was performed in each eye, and topical 0.1% dexamethasone and 1% atropine sulfate drops were administered four times a day. In addition, 5 mg of fluorouracil in 0.5-mL saline was repeatedly injected inferiorly, 180° away from the surgical site. Frequency (one to two times per day)

Subconjunctival 5-Fluorouracil-Induced Transient Striate Melanokeratosis

To the Editor. —5-Fluorouracil injected subconjunctivally in conjunction with trabeculectomy has been associated with a variety of ocular toxic effects. We have recently observed five cases of transient striate melanokeratosis following the subconjunctival injection of 5-fluorouracil after trabeculectomy (Figure). The ages of the five patients ranged from 29 to 78 years; four patients were black and one was white. All patients received a total of eight subconjunctival injections of 2.5 mg of 5-fluorouracil given on postoperative days 1, 2, 3, 4, 6, 8, 10, and 13. Two of the five patients developed corneal epithelial defects approximately 2 weeks after surgery. The epithelial defects healed completely within 1 week. The remaining three patients developed diffuse superficial punctate keratopathy in the immediate postoperative period that resolved within 3 weeks. The striate melanokeratosis was first observed 3 to 4 weeks after surgery in all patients. The pigmented epithelial lines slowly resolved over 2

Primate Trabeculectomies With 5-Fluorouracil Collagen Implants

Bilateral trabeculectomies were performed on four normal cynomolgus monkeys. Highly purified bovine skin collagen implants with either 1 mg of 5-fluorouracil or physiologic saline (one each per monkey by randomized, masked assignment) were sutured under the scleral flaps. The randomization code was not broken until all clinical and histopathologic observations had been completed. Six weeks postoperatively, the 5-fluorouracil-treated eyes had more deeply open internal trabeculectomy ostia than the control eyes; however, the intraocular pressures were indistinguishable, the filtering blebs were only minimally different, and half of each group had trace or mild anterior subcapsular lenticular changes. Histologically, a multinucleated foreign body giant cell reaction was evident in all of the collagen implants, but the 5-fluorouracil-treated eyes had less vigorous or delayed reactions compared to the control eyes. The collagen implant appears to be a poor drug delivery system in this model of glaucoma filtering surgery, because it incites a granulomatous inflammatory reaction.

Inhibition of Posterior Capsule Opacification by 5-Fluorouracil in Rabbits

An extracapsular cataract extraction was performed on both eyes of 24 rabbits. Irrigation for 10 min of the capsular bag of the left (test) eye with 8-12 cm3 of 1 litre of BSS-plus to which had been added 50 mg of 5-fluorouracil significantly inhibited proliferation of the anterior capsular epithelium as compared with the right (control) eyes identically treated except for the omission of 5-fluorouracil (p less than 0.001). Corneal endothelial counts did not differ significantly. A reduction in opacification of the posterior capsule is expected from 5-fluorouracil treatment.

Concentration Change and Activity of Fluorouracil in the External Segment of the Eye After Subconjunctival Injection-Reply

In Reply. —Dr Ball's letter correctly addressed some of the concerns that we had in extrapolating our results obtained using normal rabbit eyes to the clinical situation. The main purpose of our article was to report that 24 hours after the subconjunctival injection of 5 mg of fluorouracil, its levels in the cornea, sclera, and conjunctiva were still above the reported fluorouracil concentrations for 50% inhibition of cultured fibroblast proliferation levels, which may have clinical implications for the safe use of this drug. As expressly stated in the Comment section, it is difficult to estimate the fluorouracil levels postoperatively in the human eye with glaucoma from the results we obtained. 1 There are too many differences in the conditions between normal rabbit eyes and human eyes with glaucoma postoperatively. For example, we injected fluorouracil through the superior rectus muscle belly to minimize reflux. 1 In patients, this method of injection

Low-Dose 5-Fluorouracil and Glaucoma Filtration Surgery

We show that a 40-mg total dose of subconjunctival 5-fluorouracil after glaucoma filtering surgery can provide a success rate comparable to that demonstrated in prior studies employing a higher dose. Sixty-four eyes with poor prognoses underwent filtering surgery with postoperative subconjunctival injections of 5 mg of 5-fluorouracil daily for seven days followed by one injection 1 week later. In 75% percent of the eyes intraocular pressure stabilized at 21 mm Hg or less regardless of medications used. The majority of failures occurred within 6 months of treatment. Postoperative corneal epithelial defects occurred in 30% of the cases, conjunctival wound leaks in 6.3%. A 40-mg dose of subconjunctival 5-fluorouracil appears to be effective and may be associated with a lower incidence of postoperative complications than higher doses.

Fluorouracil therapy of intraocular Greene melanoma in the rabbit.

We evaluated the efficacy of intraocular and periocular fluorouracil treatment in an experimental iris tumor of the rabbit (Greene amelanotic melanoma). Four consecutive intravitreal injections of 1 mg of fluorouracil given twice weekly completely suppressed tumor growth in all treated eyes for six weeks if treatment was initiated 24 hours after tumor implantation. In contrast, all control eyes implanted with an equal number of Greene melanoma cells but treated with intravitreal saline developed massive tumor invasion of the iris within two weeks. Additional subconjunctival therapy following intravitreal therapy for two weeks was only slightly more effective than intravitreal therapy alone. If therapy was delayed for one week, the iris tumors became macroscopically visible and subsequent treatment with intravitreal and subconjunctival fluorouracil was of limited value in suppressing growth.

The follow up study of intra-arterial infusion chemotherapy with local vein blocking as a surgical neo-adjuvant treatment for locally advanced breast cancer.

Preoperative intra-arterial infusion neo-adjuvant chemotherapy, in combination with local vein blocking, was administered to thirty-one patients with locally advanced stage III breast cancer. The anti-cancer drugs and dosages used were 500 mg of 5-Fluorouracil (5FU), which was infused daily for 7-14 days, and 20 mg of Adriamycin (ADM), which was administered as a bolus dose twice into the subclavian and internal mammary arteries. The response rate of this method on the primary tumor was 48.4 per cent, and, histologically it was found to be as high as 90.3 per cent. The response rate of the clinical effects on the regional lymph nodes was 50.0 per cent, however, histologically, it was found to be lower than that of the primary tumor. In the long-term follow-up study the 5-year survival rate was 72.2 per cent. Thus, this method seems to be effective as a combined modality in cases of locally advanced stage III breast cancer.

上顎癌の治療 病理組織学的悪性度との関連からみた治療成績

The success of treatment of maxillary sinus carcinoma depends mainly on primary tumor control. Our treatment of maxillary sinus carcinoma is a combination of radiation, chemotherapy and surgery. After 20 Gy irradiation, the tumor is removed as much as possible, followed by intra-arterial infusion of a total dose of 2, 500mg of 5-fluorouracil and 20 Gy irradiation. Then maxillectomy is performed through the oral cavity according to Denker's operation or by extended total maxillectomy.A system for the histological grading of malignancy was applied to 38 squamous cell carcinomas from the maxillary sinus. Six different morphological parameters were evaluated with respect to the tumor cell population and the tumor-host relationship.High-grade malignancy was usually fatal, because of distant metastases. Active treatment with Denker's operation was possible in 17 patients, and 14 of them are now free of tumor, regardless of the malignancy score, with good facial appearance and function. In high malignancy score cases, the tumor has a tendency to invade, and extended total maxillectomy is safer. In low malignancy cases, even in T4 cases, 10 of 22 cases are now free of tumor.

Fluorouracil Therapy for Proliferative Vitreoretinopathy after Vitrectomy

Fluorouracil effectively inhibits epiretinal membrane formation and traction retinal detachment after vitrectomy surgery. When 0.5 mg of fluorouracil was administered intraocularly every 24 hours for seven days, traction retinal detachment two weeks after the intraocular injection of 200,000 cultured retinal pigment epithelial cells occurred in 12 of 12 control eyes but in only six of 14 eyes treated with fluorouracil (P less than .001). Four weeks after cell injection, eight of 12 eyes treated with fluorouracil had traction retinal detachments whereas 12 of 12 control eyes did (P less than .001). The height of the traction retinal detachment four weeks after intraocular injection of 200,000 cultured retinal pigment epithelial cells was reduced 50% in eyes treated with 0.5 mg of fluorouracil every 24 hours for seven days compared to control eyes (P less than .001). When the number of injected retinal pigment epithelial cells was increased to 400,000 cells and 1.25 mg of fluorouracil was administered intraocularly every 24 hours for seven days, traction retinal detachment two weeks after injection occurred in 15 of 15 eyes in the control group but in none of ten eyes in the treated group. Four weeks after cell injection, eight of eight eyes in the control group and five of five eyes in the fluorouracil-treated group had detachments and the mean height of the detachments in the two groups was equal. Autoradiography of the epiretinal membranes in eyes injected with 200,000 cultured retinal pigment epithelial cells and labeled for two hours with tritiated thymidine showed that 0.8% of the epiretinal cell nuclei were labeled two weeks after cell injection but that no labeled cells were present in the fluorouracil-treated eyes. Tritiated thymidine labeling of epiretinal cells in the fluorouracil-treated eyes was first noted three weeks after the cell injection. The presence of tritiated thymidine labeling in the fluorouracil-treated eyes correlated with an increase in the number of epiretinal cells and an increase in the incidence of traction retinal detachment.

Ocular Toxicity of Fluorouracil after Vitrectomy

The retinal and corneal toxicity of fluorouracil in the rabbit eye after lensectomy and vitrectomy depended on both the dosage and the frequency of intraocular injection and was reversible at certain dosages. All eyes in Group 1 (1.25 mg of fluorouracil every 12 hours for four days and then every 24 hours for three days) had opaque corneas by three days; these did not clear for four weeks. Histologic studies showed loss of photoreceptor outer segments and loss of ribosomes in all the retinal cells examined. The electroretinographic b-wave decreased to 0% of the baseline value (no b-wave), and did not recover after three weeks. In Group 2 eyes (1.25 mg of fluorouracil every 24 hours for seven days), corneal opacification increased to a maximum after two weeks and gradually decreased by four weeks. The electroretinographic b-wave diminished to 9.6% of the baseline value at two weeks but later recovered to 62.5% of the baseline value at three weeks. Histologic studies showed loss of photoreceptor outer segments and ribosomes at nine days; both returned to near normal after five weeks. Clinical, electrophysiologic, and histologic studies showed no toxicity in Group 3 eyes (0.5 mg of fluorouracil every 24 hours for seven days). This dosage of fluorouracil exerts a significant antiproliferative effect on injected retinal pigment epithelial cells and is well tolerated by the rabbit eye.

Cancer chemotherapy model using autochthonous large bowel cancer in rats.

Chemotherapy of methylnitrosourea-induced autochthonous large bowel cancer in rats, which is similar to that in man, was studied to evaluate the intrarectal administration or topical application of chemotherapeutic agents. Rats with large bowel tumors confirmed by endoscopic examination received an intrarectal instillation of 1 mg of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), 1 mg of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU), or 5 mg of 5-fluorouracil (ir groups), or intraperitoneal injection of 2.5 mg of 5-fluorouracil (ip group) daily for 8 weeks. All the rats, including non-treated control rats, were necropsied after the treatment. The number of large bowel tumors per rat detected by endoscopy before the treatment was mostly the same among groups, whereas that observed at necropsy after the treatment was significantly smaller in ir groups, compared to non-treated group and ip group. The tumors increased significantly in rats of non-treated group and ip group between the time of endoscopy and necropsy, but not in rats of ir groups. These results showed that the maximum tolerated dosage of the agents administered intrarectally suppressed the development of new tumors after start of the treatment and also the growth of tumors which were detected by endoscopy before the treatment.

Enhanced toxicity for mice of combinations of bacterial endotoxin with antitumor drugs.

The toxicity of Salmonella typhosa 0901W endotoxin to mice was potentiated by (per kilogram) 1 mg of colchicine, 20 mg of emetine, 100 mg of 6-mercaptopurine, 100 mg of 6-methylmercaptopurine riboside, 75 mg of methotrexate, 2 mg of sparsomycin, or 2.5 mg of vinblastine. No potentiation of endotoxin lethality was evident with simultaneously administered (per kilogram): 200 mg of cytosine arabinoside, 450 mg of dibromomannitol, 100 mg of 5-fluorouracil, 125 mg of 5-fluorouracil deoxyriboside, 8 mg of mitomycin C, 1 mg of nitrogen mustard, or 10 mg of tris(1-aziridinyl)-phosphine sulfide. With the exception of colchicine, all drugs prolonged the duration of sleep after the administration of 80 mg of hexobarbital per kg. Simultaneous injection of endotoxin with 100 mg of 6-mercaptopurine per kg, 75 mg of methotrexate per kg, or 1 mg of vincristine per kg resulted in significantly greater lethality than administration either prior to or after the drug. However when endotoxin was administered prior to 100 mg of 5-fluorouracil per kg, lethality was significantly increased. The route of administration of endotoxin and 5-fluorouracil, 6-mercaptopurine, methotrexate, or vincristine did not influence overall lethality. Pretreatment of mice with multiple doses of Escherichia coli endotoxin resulted in a significant reduction in the lethality of 6-mercaptopurine- or vincristine-endotoxin combinations, but had no influence on 5-fluorouracil- or methotrexate-endotoxin combinations. Endotoxin-pretreated mice were more susceptible to vincristine alone and more resistant to high doses of 5-fluorouracil. The lethality of 6-mercaptopurine was increased by simultaneous administration of gram-negative isolates from feces of human patients with neoplastic disease.