Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From 1973 to 1982 six children and eight adolescents with extremity melanomas were treated by local excision and adjuvant hyperthermic isolated regional perfusion with Melphalan (L-phenylalanine mustard, manufactured by Burroughs Wellcome Company, Research Triangle Park, NC). The median Breslow thickness of the melanomas was 2.7 mm (range, 1 to 15 mm). According to the M.D. Anderson classification, nine patients were in Stage IA and five were in Stage IIIB. The median follow-up period was approximately 10 years. Distant metastases developed in three patients (21%) (one patient was in Stage IA [11%] and two patients were in Stage IIIB [40%]). In two cases the development of distant metastases was preceded by local recurrence (14%). The 5-year survival rate was 93%. The 10-year survival rate was 81%. The high survival rate, even for patients with unfavorably thick melanomas, seems to be attributable to isolated regional perfusion.
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PMID:Hyperthermic isolated regional perfusion in the treatment of extremity melanoma in children and adolescents. 291 Apr 18

Cloned cell lines of human breast cancer can be growth inhibited by tamoxifen and this inhibition can be reversed by estrogen. We wondered whether tamoxifen inhibition of breast cancer followed by estradiol reversal would increase the efficacy of chemotherapy by increasing the fraction of rapidly cycling cells. We describe a clinical trial in which 110 patients were prospectively randomized to chemotherapy consisting of cytoxan 750 mg/m2 and adriamycin 30 mg/m2 on Day 1 plus 5-FU 500 mg/m2 and methotrexate 40 mg/m2 on Day 8 vs the same chemotherapy plus tamoxifen 20 mg/m2 Days 2-6 and premarin 0.625 mg Q 12-H X 3 on Day 7. Chemotherapy was given in 21-day cycles. 108 patients were evaluable. No difference exist for any important prognostic variables. The first 55 patients were randomized to a regimen in which 5-FU preceded methotrexate by 24 h; thereafter, all patients received methotrexate followed in 1 h by 5-FU. No difference in any response parameter was seen between these two 5-FU methotrexate schedules. No differences in percent of protocol chemotherapy administered or observed toxicity was seen between the 2 regimens. Objective response rate was nearly identical--57% without and 64% with additional hormones. Prior adjuvant chemotherapy with L-PAM had no observable effect on response rate, response duration or survival. In a limited number of patients with inflammatory breast cancer we saw a significantly higher response rate (93 vs 61%; P = 0.03) than in patients with recurrent metastatic disease. Time to progression (13 vs 17 months) and survival (17 vs 23 months) of responders significantly favored the treatment arm including tamoxifen and premarin. Greater benefits of additional tamoxifen and premarin were seen in partial vs complete responders. This may have resulted from lower doses of chemotherapy given to patients achieving a complete remission. An additive effect of hormones plus chemotherapy cannot be entirely excluded as the explanation for the improved results seen with the addition of tamoxifen for 4 days plus 1 day of premarin. We believe that our results suggest that further efforts to increase the efficacy of chemotherapy by perturbing tumor growth rates may be worthwhile.
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PMID:Increasing the response rate to cytotoxic chemotherapy by endocrine means. 2333 Jan 78

The effectiveness of a relatively low dose of cyclophosphamide (15 mg/kg CY), melphalan (2.5 mg/kg L-PAM) or the monofunctional form of CY (150 mg/kg MoCY) for the cure of mice bearing a large primary s.c. MOPC-315 tumor and extensive metastases has been shown to be dependent on the cooperation of the drugs' tumoricidal activity with T-cell-dependent antitumor immunity, the latter facilitated by the drug's immunomodulatory activity. Here, we have compared the curative effectiveness of three additional drugs: methyl nitrosourea (MNU), hydroxyurea (OH-urea) and bis-chloroethyl nitrosourea (BCNU). Among these drugs, only a relatively low dose of BCNU (15-20 mg/kg) was effective in curing most mice (85%) bearing a large, late stage tumor. A higher dose of BCNU (40 mg/kg, LD10) was much less effective. After an optimal dose of BCNU, the proliferative capacity of the tumor cells 24 h after therapy was reduced by greater than 97%. However, viable tumorigenic cells were still present in the primary tumor and enhanced T-cell-dependent antitumor immunity was necessary for their eradication. The cured mice were resistant to tumor rechallenge. When a low curative dose of L-PAM was followed by OH-urea, the therapeutic effectiveness was not affected, but when this dose of L-PAM was followed by a high nontoxic dose of MNU (100-150 mg/kg), the therapeutic effectiveness was diminished even though MNU was highly tumoricidal (i.e. greater than 99% inhibition of proliferative activity). Thus, BCNU appears to be similar to CY, L-PAM and MoCY in its mechanism of MOPC-315 tumor eradication. The alkylating activity of CY, L-PAM, MoCY and BCNU appears to be critical for their combined tumoricidal and immunomodulatory effects. Since BCNU is the simplest of these four drugs with respect to metabolic pathway, a further study with BCNU and related constructs may shed some light on the biochemical mechanisms of their mode of action. At least one reason for the ineffectiveness of OH-urea or MNU at either low or nontoxic high doses was poor tumoricidal or immunomodulatory activity, respectively. Thus, it seems important to consider both the tumoricidal and immunomodulatory activities of drugs when developing regimens for effective chemotherapy.
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PMID:Tumoricidal and immunomodulatory activities of drugs and implications for therapy of mice bearing a late stage MOPC-315 plasmacytoma. 323 39

At no stage of tumor growth are thymocytes from MOPC-315 tumor bearers capable of bringing about the generation of enhanced antitumor cytotoxicity when added to immunization cultures of syngeneic normal spleen cells and "autochthonous" tumor cells. However, by Day 7 after low-dose melphalan [L-PAM (L-phenylalanine mustard)] therapy of mice bearing a large (greater than or equal to 20 mm) s.c. MOPC-315 tumor, their thymocytes exhibit such activity and it persists for at least 17 additional days. The ability of thymocytes from L-PAM-treated MOPC-315 tumor bearers to bring about the generation of enhanced antitumor cytotoxicity when added to immunization cultures of normal spleen cells and MOPC-315 tumor cells is evident over a 10-fold range of responder/stimulator cell ratios, and requires the presence of the thymocytes within the first day after initiation of the 5-day immunization cultures. In addition, immunization cultures containing normal spleen cells and thymocytes from L-PAM-treated MOPC-315 tumor bearers exhibit enhanced antitumor cytotoxicity by Day 4 after culture initiation that persists for at least 3 additional days. Thymocytes from L-PAM-treated MOPC-315 tumor bearers are able to bring about the generation of enhanced antitumor cytotoxicity only in response to stimulation with autochthonous tumor cells but not in response to stimulation with unrelated allogeneic EL4 tumor cells. The apparent specificity of the enhanced antitumor immune reactivity of thymocytes from L-PAM-treated MOPC-315 tumor bearers is not the result of extensive metastasis of tumor cells to the thymus. In fact, no tumor cells were found in the thymuses of MOPC-315 tumor bearers with methods that can detect 1 X 10(3) tumor cells, indicating that if MOPC-315 tumor cells metastasize at all into the thymus, the thymuses of mice bearing a large MOPC-315 tumor contain fewer than 1 X 10(3) tumor cells. Thus, thymocytes from mice which are engaged in the eradication of a large MOPC-315 tumor display enhanced antitumor immunity in response to stimulation with the autochthonous tumor cells. Such thymocytes may prove important to the outcome of low-dose L-PAM therapy for mice bearing a large MOPC-315 tumor, since the low-dose chemotherapy requires the contribution of T-cell-dependent antitumor immunity for its therapeutic effectiveness.
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PMID:Melphalan-induced enhancement of antitumor immune reactivity in thymocytes of adult BALB/c mice bearing a large MOPC-315 tumor. 349 11

The patient was a 26-year-old male. He was admitted to our hospital with a chief complaint of hemoptysis, cough and left scrotal mass on May 9,1984. Chest X-ray film, LAG and CT revealed multiple lung, lymph node and cerebral metastases. Based on a diagnosis of testicular neoplasm, orchiectomy was performed on May 14,1984. PVB chemotherapy (Cis-diamminedichloro-platinum, Vinblastine and Pepleomycin) was administered. Because he got worse, however, he was treated with another combination chemotherapy, consisting of Methotrexate (MTX, 100 mg/m2 intravenous push (i.v.), 200 mg/m2 12-h infusion, day 1. The dose of MTX was increased with each course. Maximum dose of MTX was 900 mg/m2/day), Vincristine (1.0 mg/m2 i.v. day 1.) Actinomycin D (10 micrograms/kg i.v. days 3.4.5), Cyclophosphamide (600 mg/m2 i.v. day 3.), Adriamycin (30 mg/m2 i.v. day 8.) and Melphalan (6 mg/m2 p.o. day 8.). After 6 courses of this regimen, distant metastases disappeared or were reduced to under one tenth, and complete remission was obtained without severe side effects. The patient was in good health on March 30, 1985.
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PMID:[Case report of choriocarcinoma of testicular origin indicating marked efficacy of a combination chemotherapy of methotrexate, vincristine, actinomycin D, cyclophosphamide, adriamycin and melphalan]. 375 9

The pharmacokinetics of isolated limb perfusion were studied to see what melphalan concentrations were achieved and how effective the isolation was. Twenty-eight patients received 32 limb perfusions with heat and melphalan for locally recurrent or level V melanoma. Melphalan was given 0.75 mg/kg for axillary/popliteal or 1.2 mg/kg for femoral perfusions with heat (perfusate 42 degrees C, limb 40 degrees C) for 1 hour. Melphalan concentratives were measured by high-performance liquid chromatography in seven patients. Peak perfusate melphalan concentrations were 6.1 to 115 mg/ml, which was one to two logs higher than peak systemic concentratives of melphalan. Isolation of the perfusate circuit from the systemic circulation was better for axillary and popliteal perfusions than for femoral perfusions (P less than 0.05). Complete responses were seen in 81% of evaluable patients; long-term local control was achieved in most patients, although many developed hematogenous metastases. Toxicity included erythema and edema in all, mild leukopenia in two, neuropathy in two, and amputation was required in one patient. Improvements in surgical technique include regional anesthesia to reduce vasospasms and transcutaneous measurement of fluorescein to measure leak. Perfusion with heat and melphalan remains the treatment of choice for in-transit metastases from melanoma.
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PMID:A clinical and pharmacokinetic study of isolated limb perfusion with heat and melphalan for melanoma. 399 75

Administration of a low dose of L-PAM (0.75 mg/kg) to mice bearing a large SC MOPC-315 tumor and extensive metastases led to the development of augmented antitumor immune potential in their hitherto immunosuppressed spleen cells. Such drug-induced potentiation of antitumor immune responsiveness appeared by day 2 after chemotherapy, and it could not be further enhanced but was actually reduced by depletion of glass-adherent cells, a procedure which is effective in depleting the cells known to have inhibitory activity (i.e., macrophages and metastatic tumor cells). To establish that L-PAM can lead to selective in situ abrogation of the inhibitory effectiveness of the splenic macrophages and metastatic tumor cells, we demonstrated that incubation of immunosuppressed tumor-bearer spleen cells with a low concentration of L-PAM in vitro also resulted in augmented antitumor immune potential that could not be further augmented by depletion of glass-adherent cells. L-PAM-mediated enhancement of the antitumor immune potential of immunosuppressed tumor bearer spleen cells was due at least in part to the effects of the drug on the splenic metastatic tumor cells. Isolated tumor cells treated with a low concentration of L-PAM were not only devoid of inhibitory activity for the primary in vitro antitumor immune response by normal spleen cells, but actually manifested a strong immunostimulatory capacity. Thus, L-PAM given at a low dose enhances the development of potent antitumor immunity which brings about the eradication of a large tumorigenic load that remains after the drug has been cleared from the circulation.
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PMID:Melphalan-mediated potentiation of antitumor immune responsiveness of immunosuppressed spleen cells from mice bearing a large MOPC-315 tumor. 643 57

Following inoculation with 1 X 10(6) MOPC-315 tumor cells, a single injection of a very low dose of melphalan (L-PAM, L-phenylalanine mustard), 0.75 mg/kg, cured most of the mice bearing a day 11 large primary tumor (20 mm) and metastases, but failed to cure mice bearing a day 4 nonpalpable tumor. Treatment of mice bearing a nonpalpable tumor with the very low dose of drug compromised the ability of the mice to respond effectively to the same low dose of drug when the tumor became large (day 12). However, a nonpalpable tumor could be eradicated by treatment of tumor bearers with a low dose of L-PAM, if it was present concomitantly with a large tumor on the contralateral side. A high dose of L-PAM, 15 mg/kg, cured mice bearing either a nonpalpable or a large tumor. The eradication of the tumor induced by the high dose of L-PAM appeared to be due solely to the tumoricidal effect of the drug. On the other hand, the eradication of the tumor by the low dose of L-PAM also required the participation of antitumor immunity of the host, since subsequent injection of antithymocyte serum abrogated the curative effect of the drug in most mice. Mice cured by a high dose of L-PAM were not resistant to subsequent lethal tumor challenge. In contrast, mice cured by the low dose of L-PAM were able to reject a tumor challenge of 300 times the minimal lethal tumor dose. The results obtained with L-PAM therapy are similar to the results that we had previously reported with cyclophosphamide therapy. Thus, the timing of therapy with a low dose of drug for mice bearing a MOPC-315 tumor is critical for successful therapy. Moreover, the selection of a low dose rather than a high dose of drug to eradicate a large tumor offers the advantage that it results in long-lasting potent antitumor immunity as a consequence of the participation of host antitumor immunity in the eradication of the tumor.
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PMID:Increase in the effectiveness of melphalan therapy with progression of MOPC-315 plasmacytoma tumor growth. 655 10

A total of 241 patients with early breast cancer had serial bone scans and chest radiographs during the first two years of follow-up after primary treatment. Each patient had had a modified radical mastectomy and been found to have involved axillary nodes. They were part of a prospective randomized trial testing the use of L-phenylalanine mustard L-PAM as adjuvant chemotherapy. During the two years, these patients had a total of 832 serial bone scans and 1091 serial chest radiographs. Twenty-five patients (10.4 per cent) had bone metastases detected on sequential scanning, only 13 of whom, however, were asymptomatic at the time of the positive scan. Twelve (5 per cent) patients were found to have pulmonary metastases on routine sequential chest radiography of whom only 8 were asymptomatic at the time of the positive chest radiograph. It is concluded from this study that, apart from their usefulness in the monitoring of clinical trials, serial bone scans and chest radiographs cannot be recommended routinely in the follow-up of asymptomatic patients because of the low yield and high cost involved.
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PMID:Sequential bone scans and chest radiographs in the postoperative management of early breast cancer. 661 53

The possible influence of histologic grade, necrosis and size of invasive breast cancers on the five year survival rate of women treated in NSABP clinical trials with regimens of L-PAM (P) and L-PAM + 5-FU (PF) and for four years in those receiving L-PAM + 5-FU + methotrexate (PMF) was investigated. Generally, all regimens effected an increased survival when compared to controls that did not receive adjuvant therapy. However, this favorable response was statistically more pronounced in those women whose cancers were histologically evaluated to be poorly differentiated (histologic grade 3) and exhibited four or more regional axillary nodal metastases. Patients whose cancers were associated with 1-3 nodal metastases were not found to exhibit statistically significant responsiveness to any regimen regardless of tumor grade. Possible reasons for this dichotomy are presented. Tumor necrosis, although paralleling the results noted with histologic grade, failed to further discriminate patients who might respond to chemotherapeutic agents. Tumor size was not found to be a consistently significant indicator of chemotherapeutic responsiveness. Generally, the PF and PMF regimens were more effective than P alone in those patients exhibiting a response. These findings indicate the importance of identifying subsets of patients with breast cancer not only from a biologic but also therapeutic perspective.
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PMID:Pathologic findings from the National Surgical Adjuvant Breast Project. VIII. Relationship of chemotherapeutic responsiveness to tumor differentiation. 682 10


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