Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

16 patients with cutaneous or subcutaneous melanoma recurrence on an extremity were treated with regional perfusion with Melphalan. 18 perfusions were performed on 15 patients with stage II disease, that is with tumor growth restricted to an extremity including possible regional node metastases. All patients except two had new recurrences within the observation time. However, many of the patients had been treated surgically for recurrences once or several times previously. By comparing the length of the recurrence-free period following surgery alone with that following surgery plus perfusion in the same patients it was shown that perfusion treatment gave a significant extension of the recurrence-free time. Four perfusions were performed on patients in stage III, that is those with distant metastases. These perfusions gave a moderate or good temporary palliation as regards to tumor growths on the extremity. The traditional treatment for melanoma recurrences on an extremity has been surgical excision or less often amputation. An analysis of the literature shows that perfusion, usually combined with excision, seems to give definitely better results than surgical excision alone. There is evidence to suggest that perfusion treatment is even superior to amputation as regards survival; if so an immunological mechanism might be responsible for this effect.
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PMID:The effect of regional perfusion treatment on recurrent melanoma of the extremities. 85 20

The role of chemotherapy in influencing tumor-specific immunity to a mouse mammary adenocarcinoma was investigated. By studying different stages of tumor growth we were able to identify several factors important to drug-induced tumor regression: (1) antibody response, (2) delayed hypersensitivity, (3) sensitivity of tumor cells to immune attack and (4) tumor burden. The presence of tumor-specific delayed hypersensitivity and circulating antibody as well as specifically armed monocytes in the tumor mass characterize the T1699 adenocarcinoma. Successful chemotherapy had previously been shown to depend on prior establishment of the above immune responses. Treatment with alkylating agents was marked in all animals by abrogation of a humoral response to the tumor when drug was given early (day 7), and was associated with poor chemotherapeutic results. Later treatment (day 10) was associated with depression of antibody titers only in the minority of animals not responding to drug and prolongation of the delayed hypersensitivity response in all treated animals. Tumors recurring following initial drug-induced regression were marked by lack of delayed hypersensitivity in the host, lack of drug response and suppression of humoral immunity following treatment. Successive passage of cells from these resistant tumors led to decreasing sensitivity to chemotherapy despite established immunity on the part of the host. The selection of tumor cells resistant to immune destruction rather than drug resistance per se appeared to pay a role. Melphalan was thus able to affect both favorably and adversely the immune factors important to drug-induced regression.
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PMID:Host immune potentiation of drug responses to a murine mammary adenocarcinoma. II. Effect of melphalan therapy on the host immune system. 99

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.
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PMID:Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice. 132 3

Pentoxifylline, a methylxanthine that is used to treat veno-occlusive disease, can increase perfusion in undervascularized tissues. Addition of high concentrations, like caffeine, causes progression through radiation or drug induced G2 phase blocks, thereby limiting time for repair of DNA breaks and crosslinks. We have examined the potential of pentoxifylline to augment the effects of antitumor alkylating agents in vitro and in vivo. In MCF-7 human breast cancer cells in vitro, pentoxifylline (2 mM) present for 24 h was only slightly cytotoxic (approximately 10% cell kill at 2 mM), but when present prior to and during AA it increased the cytotoxicity of CDDP by 2 logs at 250 microM. With L-PAM in vitro, pentoxifylline was much less effective and only at a concentration of 250 microM L-PAM did 2 mM pentoxifylline increase cytotoxicity (approximately 0.3 logs). In the FSaIIC murine fibrosarcoma system, 100 mg/kg of pentoxifylline i.p. immediately prior to the alkylating agent or 50 mg/kg x 5 of pentoxifylline over 24 h with the alkylating agent given immediately after the third dose increased the tumor cell kill achieved by CDDP, carboplatin, cyclophosphamide, and thiotepa. The increase in tumor cell killing was modest (2.9-fold). Pentoxifylline in the multiple dose regimen (50 mg/kg x 5 over 24 h) was more effective than in the single dose (100 mg/kg) protocol. In the EMT6 mouse mammary adenocarcinoma, pentoxifylline (100 mg/kg daily x 5) improved the tumor growth delay produced by CDDP (3.3 mg/kg alternate days x 3), carboplatin (25 mg/kg daily x 5), cyclophosphamide (100 mg/kg alternate days x 3) and thiotepa 5 mg/kg (daily x 5). Only with cyclophosphamide, however, did the interaction appear to be large, as a 2.4-fold increase was observed.
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PMID:Efficacy of pentoxifylline as a modulator of alkylating agent activity in vitro and in vivo. 174 13

Various human tumor lines, including gastric, colonic, esophageal, pancreatic, lung and breast cancer, were transplanted in nude mice, and the effect of K18 (IgG conjugated melphalan) on them was assessed and compared with that of melphalan. Melphalan (1 mg/kg) or K18 (100 mg/kg) were administered to mice for 28 days. The tumor growth was significantly inhibited in 5 out of 6 tumors by both agents, although only the esophageal line was insensitive to both agents. Significant loss of body weight was observed in mice after treatment. K18 had no influence on body weight. These results suggested that K18 may be useful in cancer chemotherapy.
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PMID:In vivo inhibitory effect of a conjugate of immunoglobulin G and melphalan, K18, on human tumors transplanted in nude mice. 278 17

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 tumor growth delays (TGDs) observed with a series of antineoplastic agents with or without Fluosol-DA and carbogen breathing (95% oxygen, 5% carbon dioxide) in the FSaIIC fibrosarcoma are shown. All but two of eleven alkylating agents examined showed some degree of positive effect by the addition of Fluosol-DA and carbogen breathing to drug treatment. The largest effects were seen with busulfan and procarbazine. Melphalan and the nitrosoureas, carmustine, lomustine, semustine, and chlorozotocin, gave increases in TGD ranging from 2- to 6-fold with the addition of Fluosol-DA and carbogen breathing. Modest increases were seen with cytoxan and dacarbazine. Cisplatin showed no additional TGD with Fluosol-DA and carbogen breathing, and mitomycin showed a negative effect. The addition of Fluosol-DA and carbogen breathing to bleomycin treatment increased the TGD produced by 5- to 6-fold compared to the drug alone. With vincristine and etoposide at three different doses, TGDs increased 2.4- to 3-fold in combination with Fluosol-DA and carbogen breathing. Increases of 1.3- to 1.4-fold in the TGD were observed with methotrexate and 5-fluorouracil with Fluosol-DA and carbogen breathing. Adding Fluosol-DA and carbogen breathing to treatment with several of the drugs examined resulted in significant enhancement of TGD and therefore may lead to an improved therapeutic outcome when added to certain currently used clinical regimens.
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PMID:Survey of the effect of adding Fluosol-DA 20%/O2 to treatment with various chemotherapeutic agents. 310 35

We have previously shown that mice bearing a large MOPC-315 tumor can be cured by a low dose of melphalan (L-phenylalanine mustard; L-PAM) if T-cell-dependent antitumor immunity also aids in tumor eradication (S. Ben-Efraim et al., Cancer Immunol. Immunother., 15: 101-107, 1983). Here we describe the phenotype of the T-cells that are responsible for the potent antitumor immunity exhibited by the L-PAM cured MOPC-315 tumor bearers. Initially, we identified the subset of T-cells responsible for the ability of spleen cells from L-PAM-cured MOPC-315 tumor bearers to neutralize tumor growth in the local adoptive transfer assay. The tumor-neutralizing activity of spleen cells from L-PAM-cured tumor bearers was drastically reduced when the spleen cells were depleted either in vitro or in vivo of Lyt-2+ cells. On the other hand, the tumor-neutralizing activity of spleen cells from L-PAM-cured MOPC-315 tumor bearers was not reduced, but actually enhanced, when the spleen cells were depleted either in vitro or in vivo of L3T4+ cells. The Lyt-2+ T-cells, and not the L3T4+ T-cells, were also found to be important for the ability of the intact L-PAM-cured MOPC-315 tumor bearers to reject a challenge with MOPC-315 tumor cells. Specifically, treatment of L-PAM-cured MOPC-315 tumor bearers with monoclonal anti-Lyt-2.2 antibody drastically reduced the ability of the mice to reject the tumor challenge. In contrast, treatment of the L-PAM-cured MOPC-315 tumor bearers with monoclonal anti-L3T4 antibody did not interfere with the ability of the mice to reject the tumor challenge, yet the same protocol of anti-L3T4 antibody treatment abolished the ability of splenic T-cells to provide help for the generation of a primary T-cell-dependent antibody response. The resistance of the L-PAM-cured MOPC-315 tumor bearers to challenge with MOPC-315 tumor cells was also dependent on the participation of carrageenan-sensitive effector cells, most likely macrophages, in tumor eradication. However, the immunity mediated by the T-cells, independent of carrageenan-sensitive effector cells, was extremely powerful and sufficient for the rejection of a tumor challenge with at least 300-fold, and possibly even 3000-fold, the minimal lethal dose of MOPC-315 tumor cells for 100% of normal mice.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Importance of Lyt-2+ T-cells in the resistance of melphalan-cured MOPC-315 tumor bearers to a challenge with MOPC-315 tumor cells. 326 26

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

To evaluate the utility of nude mouse xenografts as preclinical drug screens, the activity of ten established chemotherapeutic agents was evaluated against seven melanoma and three ovarian carcinoma xenografts. Xenografts were established using primary explants from patients who had not received chemotherapy and serially passaged as sc tumors in nude mice. In vivo drug activities for dactinomycin, carmustine, vinblastine, melphalan, amsacrine, cisplatin, bleomycin, mitomycin, doxorubicin, and etoposide were evaluated by 4 weekly ip injections of 10% less than LD10 doses. Plots of relative tumor growth versus time were nearly log-linear. Analysis of in vivo activity was performed using percent control growth (treated/control tumor volume) and by calculation of a novel growth delay index obtained by fitting growth curves to a quadratic regression model. Both modes of data analysis identified alkylating agents (melphalan, carmustine, and mitomycin) as the most active drugs against human melanomas. Melphalan, mitomycin, and cisplatin showed the greatest activity against ovarian xenografts. However, complete tumor regressions were noted only with melphalan, mitomycin, and cisplatin against a single ovarian tumor xenograft. Correlation analysis suggested xenograft tumor growth rate was an important determinant of drug response. These results suggest that preclinical, new-drug screening with melanoma xenografts would identify drugs such as alkylating agents as active, and may not provide an advantage over murine leukemia screens. However, screening with ovarian xenografts may more closely reflect clinical drug activity. Criteria for detecting active drugs in such systems are discussed.
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PMID:Use of nude mouse xenografts as preclinical drug screens: in vivo activity of established chemotherapeutic agents against melanoma and ovarian carcinoma xenografts. 381 95


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