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

Aphidicolin, an inhibitor of DNA polymerases alpha and delta, is cytotoxic in vitro against tumor cells. The poor solubility of aphidicolin has led to the development of aphidicolin glycinate (AG; NSC 303812), a water soluble ester currently in early clinical trials. The antitumor activity of AG was investigated in a series of transplantable murine tumors in vivo. The drug demonstrated activity against the i.p. implanted B16 melanoma, producing maximum increased life spans of 75% following i.p. administration every 3 h for three doses on days 1-9. Treatment schedules involving both single injections per day on days 1-9 and multiple injections per day on days 1, 5, and 9 were less effective, indicating that this antitumor activity is schedule dependent. Similarly, greater activity was observed against the i.p. M5076 sarcoma when three daily injections were given on days 1-9 (57% increased life span) than with a single injection either on days 1-9 (36% increased life span) or on days 1, 5, 9, and 13 (inactive). Further scheduling studies in the s.c. M5076 sarcoma model showed that a 7-day infusion was superior to both a 24-h infusion and a 7-day course of three bolus treatments per day. On the assumption that DNA polymerase inhibition is the basis for this antitumor activity, inhibition of DNA synthesis in BALB/c x DBA/2 F1 mice was investigated by measuring incorporation of [3H]thymidine (20 microCi, i.v.) into DNA of spleen and jejunum. At 2 h after administration of AG, inhibition of DNA synthesis was dose dependent (median inhibitory dose, 60 mg/kg in both tissues) and was > 99% at 300 mg/kg. The inhibition was rapid in onset; AG (100 mg/kg i.p.) produced maximal (> 98%) inhibition in both tissues at 30 min. Recovery occurred in the intestine within 16 h; in spleen recovery was delayed to 24 h, and was followed by a rebound incorporation at 48 h (203%). A comparison of the inhibition of thymidine incorporation in tumor cells (B16 melanoma and P388 leukemia) and normal jejunum revealed no significant differences in the extent of inhibition or the rapidity of recovery in these tissues. The rapid recovery of DNA synthesis inhibition supports the use of prolonged infusion schedules in clinical trials, but the lack of evidence of selectivity for tumor cells suggests that AG may be of limited therapeutic value as a single agent. Thus, we evaluated AG in combination with cisplatin in an in vivo model of cisplatin refractory human ovarian cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Antitumor activity and biochemical effects of aphidicolin glycinate (NSC 303812) alone and in combination with cisplatin in vivo. 830 34

The activities of naturally occurring polyamines are exploited to enhance the antitumor activity of cisplatin. The polyamine analogue, N1,N11-bis-ethylnorspermine (BE-3-3-3) is used at subtherapeutic levels in L1210 leukemia suspension cultures and plating efficiency assays of B16 F1 melanoma cells to increase the cytotoxic effect of cisplatin seven- and ten-fold, respectively. Similar experiments in mice reveal additive effects for DBA/2J mice bearing L1210 and synergistic effects in C57/B6 mice bearing B16 F1 tumor after optimizing combination ratios. In the latter model, at a BE-3-3-3/cisplatin molar ratio of 250:1, an increased lifespan (ILS) of 56% is recorded during a 9-day dosing schedule, whereas BE-3-3-3 at the same dose caused a 21% ILS, and cisplatin only exhibited a 7% ILS. Possible reasons for differences between in vitro and in vivo activity are discussed.
 ...
PMID:Synergism of the polyamine analogue, N1,N11-bisethylnorspermine with cis-diaminedichloroplatinum (II) against murine neoplastic cell lines in vitro and in vivo. 856 36

We have previously shown that anti-Ly-6C monoclonal antibody (MAb) 2B6-F2 identifies a subset of (CBA +/- C57BL/6)F1 splenic NK-1.1+ natural T (NT) cells which kill the NK-sensitive YAC-1 target in vitro. Furthermore, these Ly-6C+ cells are responsible for 40-50% of in vitro YAC-1 killing in all mouse strains tested. In BALB/c and DBA/2 mice, these cells killed not only YAC-1 but also the NK-resistant WEHI-164 M1/16 target via a receptor that recognises a shared determinant on these targets in vitro. In the present study, the anti-tumour role of Ly-6C+ cells against the NK-sensitive B16 melanoma and NK-resistant tumours WEHI-7 T lymphoma and WEHI-164/1C fibrosarcoma was studied in vitro and in vivo. In vitro, B16, WEHI-7 and WEHI-164/1C tumour cell lines were highly sensitive to Ly-6C+ cell killing. In vivo, these same tumours showed significantly increased growth when transplanted s.c. into syngeneic mice treated with 2B6-F2 (0.05 < or = p < 0.0005), and this was most marked in the first 15 days following tumour appearance, when tumours were <15 mm in diameter. Our results show that Ly-6C+ cells play a role in controlling the growth of transplantable NK-sensitive B16 melanoma, and in BALB/c mice, at least, the repertoire of susceptible tumours is extended to include NK-resistant WEHI-7 and WEHI-164/1C. We conclude that Ly-6C+ NT cells play a role in immunosurveillance against NK-sensitive as well as NK-resistant tumours in certain strains of mice.
 ...
PMID:Ly-6C+ natural T (NT) cells mediate immune surveillance against NK-sensitive and NK-resistant transplantable tumours in certain strains of mice. 863 70

B16 melanoma has proved to be an ideal model for investigating metastasis. The parental B16F1 line grows as a localized subcutaneous tumor in C57BL/6 or DBA/2 mice. However, by means of successive intravenous transplantation, a subline B16F10 has been established. This shows preponderant lung homing when transplanted by intravenous route into C57BL/6 mice. In this paper we have shown that pentoxifylline (PTX; Hoechst), a microfilament depolymerising agent can inhibit significantly this lung homing of B16F10 cells. It also had a marginal inhibitory effect on subcutaneous tumor growth.
 ...
PMID:Inhibition of lung homing of B16F10 by pentoxifylline, a microfilament depolymerizing agent. 884 69

The tubulin-binding natural product combretastatin A-4 (CA-4) was tested for antitumor activity against fresh human tumors in vitro and 2 mouse tumors, both in vitro and in vivo. In colony forming assays using 10% fetal bovine serum, CA-4 was inhibitory in 27/40 human ovary cancers with a mean IC50 of 3.18 micrograms/mL for a 1-hour exposure (n = 35 specimens) and 0.27 microgramf1p4for a continuous exposure to CA-4 for 11-14 days (n = 5 specimens). Murine B-16 melanoma and P-388 leukemia were also highly sensitive to CA-4 in vitro with an identical IC50 value of 0.0007 micrograms/mL for continuous drug exposure for 8 days. Comparable in vitro cell culture studies performed in serum concentrations higher than 10%, revealed a significant loss of cytotoxic potency. Using the same reversed-phase HPLC technique as developed for paclitaxel, CA-4 was shown to bind to serum proteins (> or = 30,000 mw) > 99% and to albumin approximately 70%. CA-4 was only marginally active (25% increased lifespan) in DBA/2 mice bearing P-388 leukemia who were given doses of 100 mg/kg IP on either days, 1, 5 and 9 (p = 0.075 by Wilcoxon analysis) or on consecutive days 1-9 (p = 0.19 compared to control). A higher IP dose of 150 mg/kg on days 1, 5 and 9 did not delay subcutaneous B-16 melanoma tumor growth in C57/B1 mice. These findings demonstrate a substantial loss of antitumor efficacy for CA-4 in physiologic serum concentrations in vitro. No consistent antitumor activity was observed in two murine tumor models in vivo.
 ...
PMID:Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor. 891 33

Intranasal administration of 10(4) U of murine interferon (IFN)-alpha/beta prolonged the survival time of DBA/2 mice injected i.v. with 10(5) (> 20,000 LD50) IFN-alpha/beta-resistant 3C18 Friend leukemia cells (FLC). Long-term survivors rejected a second challenge with 3C18 FLC without additional IFN-alpha/beta treatment. IFN-alpha/beta administered intranasally was not effective in 3C18 FLC-challenged DBA/2 mice pretreated with antibody to IFN-alpha/beta. Recombinant human IFN-alpha BDBB, which is cross-reactive on mouse cells, also increased the survival time of 3C18 FLC-challenged DBA/2 mice. Placing 10(4) U IFN-alpha/beta twice a day into the nostrils also prolonged the survival time of DBA/2 mice with 3-day established 3C18 FLC tumors. Administration of 10(4) U IFN-alpha/beta into the nasopharynx was equally effective or more effective than an equivalent amount of IFN-alpha/beta given by the i.p or oral routes or by gavage. Intranasally administered IFN-alpha/beta also increased the survival time of C57B1/6 mice challenged i.v. with EL4 T cell lymphoma cells, DBA/2 mice challenged i.v. with L1210R B cell lymphoma cells, and C57B1/6 (H-2b) and DBA/2 (H-2d) mice challenged i.v. with B16 melanoma cells (H-2b). These results may be important in devising novel therapeutic strategies for malignant disease using type I IFN.
 ...
PMID:Intranasal administration of IFN-alpha/beta inhibits the development of visceral tumor metastases. 904 69

Studies were conducted on the hypothesis that melanoma metastasis might be initiated through the generation of hybrids comprised of cells of the primary tumor and tumor-infiltrating leukocytes. Fusion hybrids were generated in vitro between weakly metastatic Cloudman S91 mouse melanoma cells and normal mouse or human macrophages. Hybrids were implanted s.c. in the tail and mice were monitored for metastases. Controls included parental S91 cells, autologous S91 x S91 hybrids, and B16F10 melanoma cells. Of 35 hybrids tested, most were more aggressive than the parental melanoma cells, producing metastases sooner and in more mice. A striking characteristic was heterogeneity amongst hybrids, with some lines producing no metastases and others producing metastases in up to 80% of mice. With few exceptions, hybrids with the highest metastatic potential also had the highest basal melanin content whereas those with the lowest metastatic potential were basally amelanotic, as were the parental melanoma cells. A spontaneous in vivo supermelanotic hybrid between an S91 tumor cell and DBA/2J host cell was one of the most metastatic lines. Hybrids with the highest metastatic potential also exhibited markedly higher chemotaxis to fibroblast-conditioned media. Histologically, the metastatic hybrids demonstrated vascular invasion and spread to distant organs similar to that of metastatic melanomas in mice and humans. Thus previous findings of enhanced metastasis in leukocyte x lymphoma hybrids can now be extended to include leukocyte x melanoma hybrids. Whether such hybridization is a natural cause of metastasis in vivo remains to be determined; however the fusion hybrids with genetically-matched parents described herein so closely resembled naturally-occurring metastatic melanoma cells that they could serve as useful new models for studies of this complex and deadly phenomenon.
 ...
PMID:Melanoma x macrophage hybrids with enhanced metastatic potential. 962 9

Lipophilic cationic compounds such as rhodamine 123, AA1, and dequalinium chloride have been reported to constitute a new class of anticarcinoma agents based on their selective localization, accumulation, and retention within the mitochondria of certain carcinoma cells. After screening more than 1000 lipophilic cationic compounds in clonogenic assays, we found that a tellurium-containing cyanine, 3-ethyl-3'-methyl-thiatelluracarbocyanine iodide (Te), exhibits significant anticarcinoma activity. In vitro testing showed that Te was 64-fold more toxic to the carcinoma cell line CX-1 than to the normal epithelial cell line CV-1. In vivo testing showed that Te significantly prolonged the survival of mice implanted with tumors. For C57BL x DBA/2 F1 mice implanted with the mouse bladder carcinoma cell line MB49, the treated:control (T:C) ratio ranged from 250 to 268%. For Swiss nu/nu mice implanted with the human melanoma cell line LOX, the T:C ratio ranged from 176 to 270%. For Swiss nu/nu mice implanted with the human ovarian tumor cell line OVCA-III, the T:C ratio was 344%. These anticarcinoma activities warrant further investigation of Te as a potential anticarcinoma agent.
 ...
PMID:Anticarcinoma activity of a novel drug, 3-ethyl-3'-methyl-thiatelluracarbocyanine iodide (Te), a tellurium-containing cyanine targeted at mitochondria. 981 5

The success of cancer gene therapy is likely to require the targeting of multiple antitumor mechanisms. One strategy involves the use of attenuated, replication-competent virus vectors, such as herpes simplex virus type 1 (HSV-1) mutant G207, which is able to replicate in human tumor cells with resultant cell death and tumor growth inhibition, yet is nonpathogenic in normal tissue. In this study, we demonstrate that infection of established tumors with G207 also induces a highly specific systemic anti-tumor immune response. In a syngeneic, bilateral established subcutaneous tumor model, with mouse CT26 colorectal carcinoma cells in BALB/c mice or M3 melanoma cells in DBA/2 mice, unilateral intratumoral inoculation with G207 caused a significant reduction in the growth of both the inoculated and contralateral noninoculated tumors. This elicited anti-tumor response is dependent on viral infection of the tumor, as intradermal inoculation of G207 in BALB/c mice had no effect on CT26 tumor growth. Treatment of subcutaneous CT26 tumors by intratumoral inoculation of G207 induced a tumor-specific T cell response. CD8+ cytotoxic T lymphocyte (CTL) activity was generated that recognized a dominant "tumor-specific" major histocompatibility complex (MHC) class I-restricted epitope (AH1) from CT26 cells. In immune-competent animals, G207 is acting as an in situ tumor vaccine. Therefore, intratumoral G207 inoculation is able to inhibit tumor growth both by local cytotoxic viral replication in tumor cells and induction of a systemic anti-tumor immune response.
 ...
PMID:Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. 1004 91

Transfection of a variety of tumor lines with the IL-2 gene strongly reduces their tumorigenic potential when applied to either euthymic or athymic animals. To elucidate the mechanisms underlying this phenomenon, we inoculated IL-2-transfected M-3D melanoma (M-3D-IL-2) cells into DBA/2 mice immunosuppressed by gamma-irradiation. Animals thus treated developed pigmented tumors, suggesting that IL-2 transfection of melanoma cells, instead of altering their neoplastic growth properties, renders them capable of evoking a tumoricidal host response. To define the critical effector cell, we injected M-3D-IL-2 and, for control purposes, nontransfected M-3D cells into DBA/2 recipients and analyzed the injection site. We found that 1) IL-2-expressing M-3D cells induce a much stronger inflammatory reaction than wild-type cells, 2) in both instances the infiltrate consists mainly of macrophages (40-60%) and granulocytes (30-40%), and 3) only the infiltrate of M-3D-IL-2 cell deposits contains a minor fraction of NK cells (approximately 1-2%). When we reconstituted sublethally irradiated animals with various leukocyte subsets, we found that unfractionated as well as macrophage-depleted peritoneal lavage cells but not NK cell-depleted peritoneal lavage cells were able to suppress the growth of IL-2-expressing M-3D cells. In vivo leukocyte depletion experiments showed that the NK cell-depleting asialo-GM1 antiserum, but not anti-macrophage and/or anti-granulocyte reagents, restored the tumorigenicity of M-3D-IL-2 cells. Our results indicate that the inflammatory tissue response evoked by IL-2-transfected cancer cells includes the attraction and/or activation of NK cells and that, in the experimental system used, these cells are critically needed for successfully controlling cancer growth in vivo.
 ...
PMID:The tumorigenicity of IL-2 gene-transfected murine M-3D melanoma cells is determined by the magnitude and quality of the host defense reaction: NK cells play a major role. 1035 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>