Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antitumor effects of chemotherapy, recombinant human interleukin-2 (IL-2), recombinant human interferon alpha A/D (IFN alpha), allogeneic human lymphokine-activated killer (LAK) cells, and antitumor monoclonal antibody (mAb), administered alone and in various combinations, were tested in athymic nude mice carrying human tumor xenografts. Treatment began 6-18 days after i.v. or i.p. inoculation of colorectal carcinoma or melanoma cell lines, when macroscopic growths were evident. Chemotherapy consisted of two or three courses of 5-fluorouracil (5-FU) or dacarbazine. IL-2 and/or IFN alpha were administered three to five times weekly for 1-3 weeks, usually starting 2-5 days after chemotherapy. Human LAK cells were infused once or twice weekly for 2 or 3 weeks concurrently with IL-2. In some experiments, murine anticolorectal carcinoma mAb (SF25) was administered. In both tumor systems, chemotherapy alone or immunotherapy alone (IL-2, IL-2 + LAK cells, IFN alpha, IL-2 + IFN alpha +/- LAK cells) had little or no therapeutic effects. Additive effects were obtained by combining chemotherapy with IL-2 and LAK cells or with IL-2 and IFN alpha. In the majority of the experiments, the most effective combination was chemotherapy + IL-2 + IFN alpha + LAK cells. Treatment with mAb was beneficial in the colorectal carcinoma system when combined with 5-FU + IL-2 or 5-FU + IL-2 + IFN alpha. Homing experiments with radiolabeled human and mouse LAK cells injected i.v. showed increased early accumulation in the liver and lungs, whereas freshly explanted mouse splenocytes localized mostly in the spleen and liver. The tissue distribution pattern of human LAK cells was similar in normal and tumor-bearing mice (with lung metastases). These findings suggest that combination of chemotherapy with cytokines and LAK cells can be partially effective for advanced solid human tumors even in the absence of the host's T-cell immune response. Preliminary experiments showed that tumor-specific, anti-melanoma T-cell clones were effective in local (s.c.) tumor growth inhibition (Winn assay) following coinjection with the autologous tumor cells.
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PMID:Chemo-adoptive immunotherapy of nude mice implanted with human colorectal carcinoma and melanoma cell lines. 159 37

The hamster Greene melanoma (HGM), implanted into the anterior chamber (AC) of a rabbit eye, has previously been used as a model for testing experimental therapies against human uveal melanomas. Even without therapy, the tumor showed necrosis and hemorrhages 8-10 days after inoculation. These changes could interfere with the interpretation of the results of experimental therapies. In 8 rabbits, a piece of HGM was implanted subcutaneously, and after 4 weeks, HGM was also implanted in the AC of the eye. In these eyes, tumor growth in the AC slowed down, and more necrosis and hemorrhages were found clinically and histologically as compared to 8 rabbits without previous subcutaneous implantation of HGM. In spite of the long use of this tumor and frequent transfer, the tumor cells did not lose their antigenic potential.
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PMID:Hamster Greene melanoma implanted in the anterior chamber of a rabbit eye: a reliable tumor model? 160 97

Tricyclic antidepressants, such as amitriptyline (Elavil), and the nontricyclic agent, fluoxetine (Prozac), bind to growth-regulatory intracellular histamine receptors, associated with anti-estrogen binding sites in microsomes and nuclei. The prototype anti-estrogen binding site/intracellular histamine receptor ligand, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, inhibits normal cell proliferation in vitro but stimulates tumor growth in vivo. Because of their structural similarity to N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, we carried out studies to determine whether amitriptyline and fluoxetine stimulate tumor growth and/or development in rodents at concentrations relevant to the treatment of human depression (equivalent human dose range, approximately 100-150 mg/day for amitriptyline and approximately 20-80 mg/day for fluoxetine). All experiments were performed blinded. In studies of growth stimulation of transplantable syngeneic tumors, groups of mice were inoculated s.c. with C-3 fibrosarcoma cells or given i.v. or s.c. injections of B16f10 melanoma cells, followed 24 h later by daily i.p. injections of saline, amitriptyline, or fluoxetine. Tumor latency (fibrosarcoma), aggregate tumor weight (s.c. injected melanoma), or time to death from pulmonary metastasis (i.v. injected melanoma) was determined; drug-induced stimulation of DNA synthesis in C-3 fibrosarcoma cells in vitro was correlated with tumor growth acceleration in vivo. In a mammary carcinogenesis model, the effects of chronic saline, amitriptyline, or fluoxetine administration on the rate and frequency of development of mammary tumors in rats fed dimethylbenzanthracene (DMBA) were compared. Eight of 20 amitriptyline- or fluoxetine-treated mice developed fibrosarcoma tumors by day 5, as compared to none of 20 saline controls (P less than 0.002). Similarly, 20 of 21 DMBA-treated rats receiving the antidepressant drugs developed 33 mammary tumors by week 15 as compared to 5 tumors in 4 of 7 DMBA-treated rats receiving saline (P less than 0.001). For both models, tumor latency decreased 30-40% and, in the DMBA model, tumor frequency increased greater than 2-fold in the antidepressant-treated rats as compared to controls. Stimulation of fibrosarcoma growth in vivo correlated with a corresponding bell-shaped drug-induced increase in DNA synthesis in vitro. While the median time to death from pulmonary metastases did not differ among groups given i.v. injections of melanoma cells, a significant (P less than 0.01) stimulation of growth of s.c. injected melanoma was observed in mice receiving the antidepressants.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses. 161 49

The effects of two new Ru(III) complexes, [mer-RuCl3(DMSO)2Im] degrees and Na[trans-RuCl4(DMSO)Im], were investigated on primary tumor growth and on the survival time using three solid metastasizing tumors of the mouse: Lewis lung carcinoma, B16 melanoma and MCa mammary carcinoma. Na[trans-RuCl4(DMSO)Im] appears to be the most promising compound, in that: (1) it is soluble in water and therefore easy to handle in comparison with the neutral species [mer-RuCl3(DMSO)2Im]degrees or to the already described BBR2382; (2) similarly to cisplatin, though at a lower level, it reduces tumor growth in its primary site in each tumor model employed; (3) unlike cisplatin, it increases the life span of tumor-bearing hosts in all tumors used, independently of the effects on primary tumor growth; and (4) it is also effective in reducing spontaneous metastasis formation when the effects on primary tumor growth are completely absent. Dimethylsulfoxide (DMSO), used for solubilizing poorly water-soluble compounds (i.e. [mer-RuCl3(DMSO)2Im]degrees) or for stabilizing the compound in the solution before injection (i.e. Na[trans-RuCl4(DMSO)Im]), reduces the anti-tumor potency. Conversely, the antitumor effects of Na[trans-RuCl4(DMSO)Im] are more pronounced in mice hydrated with isotonic saline. We conclude that Na[trans-RuCl4(DMSO)Im] is a good candidate for further investigations aimed at ascertaining the mechanism of the anti-metastatic activity and of the positive effects on survival time of mice bearing solid metastasizing tumors.
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PMID:Effects of the Ru(III) complexes [mer-RuCl3(DMSO)2Im]degrees and Na[trans-RuCl4(DMSO)Im] on solid mouse tumors. 162 12

Ilmofosine (BM 41.440, 1-hexadecylthio-2-methoxymethyl-rac-glycero-3-phosphocholine) is a synthetic alkyl lysophospholipid analog with activity against a variety of tumor models in vitro and in vivo. The i.v. form is presently undergoing early clinical investigation in phase I trials. In order to help define types of tumors that might be clinically sensitive to this agent we have studied the anti-tumor effects of ilmofosine against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 1.0-30 microgram/ml were used in continuous incubations experiments. Of 348 specimens tested, 134 (39%) were evaluable for determination of tumor growth modulating activity. The most common tumor types recruited included non-small cell lung, breast, colorectal, ovarian, renal cell cancer and melanoma. A concentration-dependent increase in the frequency of inhibited tumor specimens was observed with 6/134 (4%) sensitive specimens at 1 microgram/ml as compared with 113/133 (85%) sensitive specimens at 30 micrograms/ml (p less than 0.0000005). We conclude that ilmofosine is active against a variety of tumors in vitro. Clinical phase II trials with ilmofosine including the tumor types with in vitro sensitivity are warranted if adequate plasma concentrations of this agent can be reached in patients.
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PMID:Preclinical activity of ilmofosine against human tumor colony forming units in vitro. 162 15

Laminin is a basement membrane glycoprotein that has diverse biological activities. A sequence on the A chain containing IKVAV (Ile-Lys-Val-Ala-Val) has been shown to promote neurite outgrowth, cell adhesion, and tumor growth and metastasis. Here we have determined the structural requirements of this synthetic peptide for biological activity. Twelve-amino acid-long all-L- (LAM-L) and all-D-peptide (LAM-D) segments as well as an alternating D- and L-amino acid-containing peptide (LAM-DL), which included the IKVAV sequence (residues 2097-2108), were synthesized. Circular dichroism spectral analysis revealed a mirror image conformation of LAM-D and LAM-L with mainly beta-sheet and to a minor extent alpha-helical structure. LAM-DL did not exhibit any significant ordered conformational features. LAM-D and LAM-L showed similar cell attachment activities for rat pheochromocytoma cells (PC12), whereas LAM-DL was inactive. A peptide analog with randomized IKVAV sequence (LAM-RM) was also inactive. A similar trend was observed in competition experiments of the four peptides with laminin in analogous cell attachment assays. In in vivo experiments, both LAM-D and LAM-L were capable of increasing tumor growth when subcutaneously injected into mice with murine melanoma cells B16F10. Results indicate that the conformational status of the IKVAV domain is a contributing factor in determining the biological activity but that there is no strict requirement for a specific chirality. There is a likely sequence specificity to the IKVAV region.
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PMID:The all-D-configuration segment containing the IKVAV sequence of laminin A chain has similar activities to the all-L-peptide in vitro and in vivo. 162 12

The antitumor effects of recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA) were assessed in tissue culture and in a nude mouse model. Mismatched dsRNA did not show a direct antiproliferative effect against the human malignant melanoma cell line, BRO, in tissue culture. However, treatment of the BRO cells with up to 1000 units/ml rIL-2 in culture showed a slight increase in growth rate. Combined rIL-2/mismatched dsRNA treatment also demonstrated a similar slight enhancement of growth. Nude mice bearing subcutaneous tumors were treated by intraperitoneal injection of low doses (5000-20,000 units) of rIL-2 and mismatched dsRNA (500 micrograms). The in vivo tumor growth was significantly inhibited by the combined treatments (P less than 0.05) and survival was significantly increased (P less than 0.05). Measurement of cytotoxicity using splenocytes from treated animals showed significant augmentation of lytic activity against natural killer (NK)-sensitive YAC-1 cells in all rIL-2/mismatched dsRNA treatment groups, compared to the individual treatments or controls (P less than 0.05). Cytotoxicity of the splenocytes against the NK-resistant BRO cells was also augmented in animals treated with mismatched dsRNA and the highest rIL-2 dose utilized here (P less than 0.01). Renal, liver, and hematological toxicity was evaluated by measurement of blood urea nitrogen, creatinine, serum asparrtate aminotransferase, and a complete blood count with differential. There were no significant differences in these parameters in any of the treatment groups. Similarly, no differences in weight of the animals was seen in any treatment group. These results indicate that the combination of low-dose rIL-2 and mismatched dsRNA can potentiate host-mediated antitumor effects, yielding increased survival, without significant toxicity.
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PMID:Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft. 163 50

Two phenotypic parameters, aberrant expression of protein kinase C and tumor cell-induced platelet aggregation (PA), have been correlated with abnormal growth behavior and metastatic potential of tumor cells. We recently observed that N,N,N-trimethylsphingosine (TMS) and N,N-dimethylsphingosine (DMS), but not sphingosine (SPN), had an inhibitory effect (via blocking of transmembrane signaling) on the growth of various human tumor cell lines in vitro as well as in vivo in nu/nu mice (K. Endo et al., Cancer Res., 51: 1613-1618, 1991). We therefore investigated the effects of TMS, DMS, and SPN on (a) PA induced by ADP and thrombin; (b) PA induced by melanoma cell line B16/BL6; and (c) experimental lung colonization as well as spontaneous lung metastasis of BL6 cells in syngeneic C57BL/6 mice. In experiments on agonist-induced PA, TMS inhibited PA and ATP secretion 5-fold more strongly than DMS or SPN. This effect may be based on the inhibition of Mr 47,000 platelet protein phosphorylation and/or inhibition of phosphatidylinositol turnover as a transmembrane signaling pathway in platelets. Tumor cell (BL6 melanoma)-induced PA and ATP secretion were also strongly inhibited by TMS, but not by DMS or SPN. Unlike ADP- or thrombin-induced PA, BL6 cell-induced PA was not inhibited by Calphostin-C (a potent protein kinase C inhibitor) or cilostazol (a potent inhibitor of PA based on inhibition of cyclic AMP phosphodiesterase). Since many previous studies suggested that the ability of tumor cells to induce PA is related to the degree of malignancy (e.g., metastatic potential) of tumor cells, we studied the effect of TMS on lung metastatic potential. Three independent sets of experiments, as described below, all showed clear inhibition of lung metastasis by administration of TMS: (a) i.v. coinjection of BL6 melanoma cells and TMS; (b) i.v. injection of TMS and, 1 h later, BL6 cells; (c) spontaneous metastasis to lung from s.c. BL6 tumor (TMS administered after establishment of tumor, followed by resection of tumor). In comparison to tumor growth inhibition produced by TMS or DMS, inhibition of melanoma metastasis by TMS is obvious at lower doses.
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PMID:Cell membrane signaling as target in cancer therapy. II: Inhibitory effect of N,N,N-trimethylsphingosine on metastatic potential of murine B16 melanoma cell line through blocking of tumor cell-dependent platelet aggregation. 165 77

Taxotere (RP 56976; NSC 628503; N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol) is a new microtubule stabilizing agent. It is obtained by semisynthesis from a noncytotoxic precursor extracted from the needles of the tree, Taxus baccata L. Taxotere was evaluated for antitumor activity against a variety of transplantable tumors of mice. Taxotere had no marked schedule dependency and was found active by the i.v. and the i.p. routes. Upon i.v. administration, 9 of 11 tumor models tested responded to Taxotere. B16 melanoma was found highly sensitive to Taxotere, with a tumor growth inhibition of 0% and a 3.0 log10 tumor cell kill at the maximum tolerated dose. In the same trial, taxol produced only a 1.1 log10 tumor cell kill at the maximum tolerated dose. Taxotere cured early stage pancreatic ductal adenocarcinoma 03 (6 of 6 cures) and colon adenocarcinoma 38 (7 of 7 cures). It also effected greater than 80% complete regressions of advanced stage disease with both tumors. Taxotere was active against early and advanced stage colon adenocarcinoma 51, with 2.3 and 1.7 log10 cell kill, respectively. Four other tumors responded to a lesser extent: Lewis lung (5.5% tumor growth inhibition), Glasgow osteogenic sarcoma (27.2% tumor growth inhibition), L1210 and P388 leukemias (70 and 54% increase in life span, respectively). Because of its good preclinical activity and its unique mechanism of action, Taxotere has entered Phase I clinical trials.
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PMID:Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. 168 23

Previous reports on the slower growth of tumors in senescent mice have suggested a decrease in tumor angiogenesis in these animals, but such an observation has not yet been documented quantitatively. In this study, we report the relative amount of tumor angiogenesis and tumor volume for two different types of tumor in 11 young (8-9-wk old) versus nine older (19-mo old) male C57BL/10 mice. B16 melanoma or SP1 methylcholanthrene-induced fibrosarcoma cells were injected into the ventral skin of mice. After 3 days, the mice were killed and the injection sites were examined for angiogenesis surrounding the tumor (centrally directed tumor angiogenesis), nerve-associated angiogenesis, and tumor volume. In the older mice, there was significantly less centrally directed tumor angiogenesis for both tumors tested, and nerve-associated angiogenesis was decreased for B16 melanoma. The mean tumor volume for the B16 implants was smaller for the older animals, but the mean SP1 tumor volumes were identical for both age groups. These findings support the hypothesis that tumor growth in older animals is associated with less formation of new blood vessels, and this may explain the slower tumor growth observed in aged animals with certain experimental tumors.
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PMID:Effect of host age on tumor-associated angiogenesis in mice. 168 82


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