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)

As the observation times of current studies using adjuvant chemotherapy in the treatment of operable stage II breast cancer lengthen, the probability of significantly reducing the high risk of developing metastases associated with this stage of the disease is also increasing and should be reflected in improved cure rates. The theoretical basis, prerequisites and presently available results for adjuvant chemotherapy of breast cancer are discussed. Adjuvant combination chemotherapy provides better results than monochemotherapy with Alkeran. While earlier results suggested that adjuvant chemotherapy is especially effective in premenopausal women, newer studies and analyses indicate that appropriate dosage and consistent administration of chemotherapy are of decisive importance. Exact determination and documentation of the tumor stage, and especially the regional lymph node status, is the most important factor in determining the indication for adjuvant chemotherapy. Adjuvant chemotherapy is still best with many unsolved problems. These include the duration, necessary intensity based upon risk factors, and short- and long-term side effects.
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PMID:[Results of, and indications for adjuvant chemotherapy in breast cancer]. 726 39

In an open study of unresectable liver tumours, isolated regional perfusion with hyperthermia and cytotoxic drugs has been tested in 29 patients. Four patients had primary hepatocellular cancer, 10 patients had metastases from malignant melanoma, remaining from breast cancer, colorectal cancer, midgut carcinoids and miscellaneous primaries. At laparotomy the proper hepatic artery and portal vein were canulated and connected to a pump oxygenator. The inferior vena cava was canulated with a triple lumen catheter (Perfufix) allowing for porto-caval shunting, drainage of lower body and renal veins to the heart and separate drainage of liver veins to the pump oxygenator. Liver perfusion was performed with a mean flow of 900 ml per min. Melphalan and cis-platinum 0.5 mg/kg body-weight were added to the perfusate for 1 h after liver temperature reached 40 degrees C. Four patients died within 30 days of perfusion due to multiple organ failure. These patients had more than 50% of liver volume occupied by cancer. All surviving patients developed reversible hepato- and renal toxicity. Partial tumour regression was registered in 20% of the patients. Five patients have survived more than three years. Hyperthermic liver perfusion is feasible but in patients with massive liver tumour, there is a significant risk of developing multiple organ failure.
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PMID:Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy. 795 89

We have previously shown that depletion of TCR-V beta 8+ T cells by treatment with mAb reduces the curative effectiveness of low dose melphalan (L-phenylalanine mustard; L-PAM) for mice bearing a large MOPC-315 tumor and extensive metastases. Here we show that V beta 8+/CD8+ T cell lines derived from mice that are in the process of immune-mediated eradication of a large MOPC-315 tumor as a consequence of low dose L-PAM therapy (L-PAM TuB mice) are capable of mediating tumor eradication in vivo upon adoptive transfer. Analysis of the possible mechanisms through which these cell lines bring about tumor eradication revealed that the V beta 8+/CD8+ cells can exert in vitro a potent lytic activity and secrete large amounts of IFN-gamma. Both of these activities can be triggered by the MOPC-315 but not the MOPC-104E plasmacytoma and are restricted by the MHC class I H-2Kd molecule. In vivo neutralization of IFN-gamma by treatment with mAb was found to cause a noticeable delay in tumor rejection in mice subjected to adoptive chemoimmunotherapy with low dose L-PAM and V beta 8+/CD8+ cells; however, all tumors did regress after initial growth. Thus, the V beta 8+/CD8+ cells use an IFN-gamma-dependent mechanism for the realization of their in vivo tumor-eradicating immunity. However, an IFN-gamma-independent mechanism, most likely involving direct V beta 8+/CD8+ CTL activity, is apparently also used.
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PMID:Insight into the mechanism of TCR-V beta 8+/CD8+ T cell-mediated MOPC-315 tumor eradication. 808 90

We have recently demonstrated the importance of V beta 8+/CD8+ cells for the curative effectiveness of a suboptimal low dose (0.75 mg/kg) of melphalan (L-phenylalanine mustard; L-PAM) for mice bearing a large s.c. MOPC-315 tumor and extensive metastases. Here we show that staphylococcal enterotoxin B (SEB), which is known to selectively stimulate T cells expressing members of the TCR-V beta 8 gene family, substantially improved the curative effectiveness of the suboptimal dose of L-PAM for mice bearing a large MOPC-315 tumor. Moreover, treatment of mice with mAb F23.1 (anti-V beta 8) abrogated the in vivo therapeutic effect of SEB for low dose L-PAM-treated MOPC-315 tumor bearers (L-PAM TuB mice). Analysis of the effect of SEB on the tumor-infiltrating lymphocytes (TILs) demonstrated that the SEB-mediated therapeutic effect was associated with a significant increase in: 1) the percentage of V beta 8+ cells among the CD8+ T cells that accumulated in the s.c. tumor nodules, 2) the total number of V beta 8+/CD8+ cells present per tumor on day 4 after low dose L-PAM therapy, and 3) the ability of the TILs to lyse MOPC-315 tumor cells in vitro in a short term assay. Furthermore, treatment of mice with mAb F23.1 abolished the ability of SEB to render the TIL population of L-PAM TuB mice more cytotoxic in vitro for MOPC-315 tumor cells. Thus, the SEB-mediated improvement in the therapeutic outcome of low dose L-PAM therapy for mice bearing a large MOPC-315 tumor may be due in part to SEB-mediated increase in the contribution of the V beta 8+ T cells to tumor eradication through enhancement in the magnitude of the anti-MOPC-315 lytic activity exhibited by the TIL population.
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PMID:Cooperation between staphylococcal enterotoxin B and low dose melphalan in the cure of mice bearing a large MOPC-315 tumor and extensive metastases. 814 32

Between January 1993 and December 1996, 21 children with advanced solid tumors were entered in a dose-escalating study of high-dose sequential chemotherapy followed by autologous stem cell transplantation. The diagnoses included neuroblastoma (NB) for 13 patients; Ewing's sarcoma (ES) for six patients and osteosarcoma for two patients. Nine patients received therapy as consolidation for primary metastatic disease, and 12 patients had had previous relapses. Treatment consisted of CY given i.v. at a dose of 7 g/m2 on day 1, followed by G-CSF until myeloid recovery. After 3 weeks of rest, all patients were given thiotepa i.v. on days 22-24. The total dose of thiotepa was 450 mg/m2 in three patients, 600 mg/m2 in six patients, and 750 mg/m2 in 12 patients. Melphalan was given i.v. at a dose of 180 mg/m2 i.v. on day 27 followed by stem cell infusion on day 28. Major toxic reactions included stomatitis, esophagitis, diarrhea and dermatitis. Three patients died of treatment-related complications. Twelve patients have had a relapse. Six patients (five with NB and one with ES) are alive in continuous remission 5-50 months (median 36) after transplantation. The results of this study show that it is feasible to administer high-dose sequential chemotherapy to children with advanced solid tumors.
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PMID:High-dose sequential chemotherapy and autologous stem cell reinfusion in advanced pediatric solid tumors. 946 76

In an attempt to improve tumor response and survival among patients with colorectal cancer metastases confined to the liver, we developed an experimental (rats and pigs) and clinical isolated hepatic perfusion (IHP) technique to exploit maximally the steep dose-response relation of may anticancer drugs. In this overview we present our experimental and clinical results with mitomycin C (MMC) and melphalan (L-Pam). In rats, treatment with a four times higher maximally tolerated dose (MTD) of MMC during IHP compared to hepatic artery infusion (HAI) resulted in higher, more effective intratumoral concentrations of MMC. As a result, only in the IHP-treated rats were complete remissions observed and long-term survival achieved. Hepatotoxic side effects were minimal and transient in all animals. In the clinical phase I/II study with MMC 30 mg/m2 administered as a bolus in the isolated circuit, two of nine patients had a complete remission, with a median survival of 17 months. Four patients developed venoocclusive disease (VOD) of the liver, and as a result one patient died. Therefore we consider MMC unsuitable for further IHP studies. Meanwhile experiments in rats showed that IHP with the L-PAM MTD of 12 mg/kg was even more effective than MMC and did not cause hepatotoxic side effects. In the phase I/II dose-findings study with L-PAM in IHP, the MTD in humans was approximately 3.0 mg/kg. As in the rats, systemic toxicity was dose-limiting. The median survival of the whole group was 18 months. We have started a phase II study of L-PAM in IHP with a fixed dose of 200 mg L-PAM to determine if IHP can significantly increase the median survival and complete remission rate compared to other treatment modalities. Results from this study are expected by the end of 1997.
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PMID:Phase I/II studies of isolated hepatic perfusion with mitomycin C or melphalan in patients with colorectal cancer hepatic metastases. 967 Feb 71

Tumor necrosis factor (TNF) is a highly cytotoxic cytokine. However, due to its severe side effects, the only clinical situation allowing its administration in humans is isolated limb perfusion (ILP). Early studies have shown that TNF alone is of limited efficacy even at high doses via ILP, and that a chemotherapeutic agent needs to be added. The most commonly used drug in this setting is melphalan which is considered to be synergistic with TNF. However, since melphalan has not been commonly used in sarcoma, we believed that confirmation of its synergistic effect with TNF in an experimental sarcoma model could prove valuable for future drug choice. B16F10 melanoma and CT26 colon carcinoma cells were injected subcutaneously (s.c.) into mice, while GF fibrosarcoma cells were injected s.c. into the hindleg of Wistar rats. The animals were then divided into four treatment groups: TNF alone, melphalan alone, TNF and melphalan, and 0.9% NaCl controls. Mice were treated with intraperitoneal injections and rats by ILP. TNF dosage was 20 microgram for mice and 200 microgram for rats. Melphalan was given at 5-10 mg/kg for both mice and rats. Results showed synergism of TNF and melphalan in both modes of therapy. In the systemic administration groups (mice carrying B16F10 and CT26 tumors), tumors increased in size in all but the combined TNF-melphalan group. In the regional delivery groups (rats carrying GF sarcoma cells treated via ILP), there was a 16% decrease in tumor volume in rats treated with TNF alone, a 29% decrease in rats treated with melphalan, and a 75% decrease in the combined TNF-melphalan group. In conclusion, TNF and melphalan proved to be highly synergistic in both systemic and regional delivery. This fact makes melphalan an adequate choice for TNF perfusion in advanced limb malignancies.
Invasion Metastasis 1997
PMID:Synergism of tumor necrosis factor-alpha and melphalan in systemic and regional administration: animal study. 977 89

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.
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PMID:Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy. 1147 32

Isolated hepatic perfusion (IHP) with melphalan is used for patients with nonresectable metastases confined to the liver. To improve the efficacy of IHP and to reduce the toxicity to the liver, reversion (retrograde perfusion) of the bloodstream through the liver in a rat model was studied. For liver tumor induction male WAG/Rij rats were inoculated with CC531 cells, a colorectal tumor cell line. After 11 to 12 days the tumor-bearing rat livers were perfused by single-pass perfusion through either the portal (orthograde) or caval vein (retrograde) for different time periods. During perfusion melphalan (160 Schultze) was infused in the hepatic artery. Melphalan concentrations were measured by high-performance liquid chromatography. A rapid extraction of melphalan by the liver occurred in the first 5 min, reaching steady state after 10 to 20 min for both perfusion directions. The melphalan concentration of the outflow perfusate was significantly higher in the retrograde perfusion compared with the orthograde perfusion. The melphalan content of the tumor tissue was unaffected by perfusion direction at any time point. To the contrary, the melphalan uptake in liver tissue was strongly influenced: the melphalan content after 40-min retrograde perfusion was 12% of that after orthograde perfusion. The average tumor/liver concentration ratio was 6 for orthograde perfusion and 30 for retrograde perfusion. In conclusion, retrograde IHP with continuous melphalan infusion in the hepatic artery provides a high tumor uptake of melphalan with potentially reduced liver toxicity compared with orthograde IHP.
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PMID:Reduced liver uptake of arterially infused melphalan during retrograde rat liver perfusion with unaffected liver tumor uptake. 1238 59

Isolated limb perfusion with Melphalan is the best treatment option to control symptomatic multiple small in-transit metastases. When lesions are bulky, Isolated Limb Perfusion (ILP) with Tumor Necrosis Factor (TNF) + Melphalan is superior as in soft tissue sarcoma. TNF changes the pathophysiology, greatly enhances the uptake of Melphalan and destructs selectively the vasculature of large tumors. To date, ILP is not indicated in an adjuvant setting.
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PMID:The role of isolated limb perfusion for melanoma confined to the extremities. 1274 14


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