Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirty patients with metastatic malignancy of various types were treated with cis-diamminedichloroplatinum(II) (DDP) administered by continuous infusion for 120 hours. The starting dose was 20 mg/m2/day (100 mg/m2/course) and was escalated by stages to 40 mg/m2/day (200 mg/m2/course). Dose-limiting toxicity was observed at 30 mg/m2/day (150 mg/m2/course), manifested as marrow suppression and particularly thrombocytopenia in 13 of 14 patients evaluated at doses greater than or equal to 30 mg/m2/day. The gastrointestinal toxicity characteristic of bolus treatment schedules was less intense but was cumulative and dose-related. Renal toxic effects developed in five of 30 patients in spite of adequate hydration and daily diuretic therapy. Peripheral neuropathy developed in the only two patients who received four courses of continuous-infusion DDP. Antitumor effects were observed in six patients (oral cancer, two; lymphoma, one; prostatic cancer, one; hepatoma, one; and bronchogenic carcinoma, one). The recommended starting dose for continuous venous infusion therapy with DDP is 30 mg/m2/day for 5 days.
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PMID:Phase I study of cis-diamminedichloroplatinum(II) administered as a constant 5-day infusion. 625 73

Phase II study of cis-diaminedichloroplatinum(II) (CIS-DDP) administered intravenously was performed in 77 patients with urologic malignancies for the evaluation of clinical responses and adverse effects. The eligibility of the patients and evaluation of response were carried out according to the general criteria proposed by Drs. Koyama and Saito. Out of 85 patients, entered in this phase II study, 77 patients were considered evaluable. Complete responses were seen in 4 patients, 3 testicular tumor and 1 bladder cancer. Partial response were obtained in 24 patients; 10 bladder cancer, 8 testicular tumor, 5 prostatic cancer, and 1 renal cell carcinoma. Overall response rates were 73.3% in testicular tumor, 50.0% in bladder tumor, 20.8% in prostatic cancer, and 7.7% in renal cell carcinoma. Incidences of toxicities were noted in the gastrointestinal tract. Nausea, vomiting, anorexia, abdominal pain, and diarrhea were observed in 78.5% of the patients treated with CIS-DDP. Myelosuppression, lassitude, renal and hearing dysfunction were other prominent adverse effects.
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PMID:[Phase II study on cis-diamminedichloroplatinum (II) by a collaborative study]. 689 91

Combined therapies of cisplatin and radiation have resulted in clinical reports of apparent efficacious control of locoregional cancer and enhanced survival. Mechanisms of interaction between platinum and radiation that may explain these clinical observations all have in common the prediction that higher concentrations of platinum in all tumor cells close in time to irradiation should lead to greater potentiation of radiation-induced killing of those cells. Cisplatin is thus viewed as providing some radiation-equivalent, or a radiation dose-effect factor, for sterilization of tumors. One disease site that has not been well investigated for response to cisplatin plus radiation therapy, but that could benefit from it, is locally advanced prostate cancer. A body of literature now supports the view that local control of stage C (T3, N0, M0) prostate cancer is correlated with disease-free survival. This correlation makes prostate cancer a candidate for potentially achieving improved cure rates following local tumor sterilization by combining cisplatin with radiation therapy. The need and approaches to optimize delivery of cisplatin within tumor tissue is explored. Increasing cisplatin concentration to all the cells of a tumor, i.e., homogeneously delivering systemic high-dose cisplatin, should benefit the efficacious response otherwise expected for cisplatin combined with radiation. Strategies to increase the homogeneity of cisplatin delivery to a tumor are considered to be those that increase perfusion to that tumor. Vasoactive agents used in anticancer protocols are especially considered for their potential value in serving to increase tumor perfusion. These protocol-inclusive agents include certain cytokines and L-arginine antagonists, and should be better managed and accepted in practice compared to other vasoactive agents that need to be developed as specific additives to protocol designs.
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PMID:Platinum drug delivery and radiation for locally advanced prostate cancer. 751 Nov 36

There have only been a few studies of chemo-endocrine therapy compared with endocrine therapy alone in newly diagnosed prostate cancer patients. We assessed the effects of these two therapies by comparing long-term survival rates. One hundred and twenty-nine patients were entered in this study between November 1977 and March 1992. Seventy-seven patients were treated with endocrine therapy alone. Other 52 patients received chemo-endocrine therapy, which included orchiectomy and/or diethylstilbestrol diphosphate (DES-DP) plus Cisplatin, with or without other cytotoxic agents. All patients had bone metastasis at the beginning of the study. There was a significant difference in survival between patients who received endocrine therapy and chemo-endocrine therapy (P = 0.0078). That is, survival rate was superior for the chemoendocrine therapy patients throughout the entire follow-up period. These data suggest that early chemo-endocrine therapy containing Cisplatin, with or without maintenance chemotherapy, is a potentially effective treatment for newly diagnosed metastatic prostate cancer and is worth further investigation via a randomized trial.
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PMID:Chemo-endocrine therapy in patients with stage D2 prostate cancer. 784 67

Cisplatin is one of the most commonly used chemotherapeutic agents. However, ototoxicity, in particular, damage to the outer hair cells of the cochlea, is one of its major side effects. Otoacoustic emissions are acoustical signals that originate from the contractile activity of the outer hair cells. They are transmitted from the cochlea to the external ear canal via the middle ear apparatus. Testing is quick, painless, objective, and non-invasive. Distortion-product otoacoustic emissions (DPOAEs) are one of the evoked types of otoacoustic emissions. They are quite sensitive to any insult to the outer hair cells, even before damage is manifested in pure tone audiometry (PTA). A patient, who was on cisplatin chemotherapy due to prostate cancer, was monitored periodically for ototoxicity using DPOAEs and PTA. DPOAEs were found to detect ototoxicity one course of chemotherapy earlier than PTA during cisplatin chemotherapy. The clinical application and sensitivity of DPOAEs in monitoring ototoxicity were discussed.
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PMID:Monitoring of cisplatin ototoxicity by distortion-product otoacoustic emissions. 880 38

Conventional chemotherapy has had very limited success in the control of hormone-refractory prostate cancer. Methylxanthine derivatives, such as pentoxifylline (PTX), are known to abrogate the G2 block and enhance the toxicity of ionising irradiation and chemotherapeutic agents. It is now also established that late addition of the cytotoxic drug after irradiation under conditions of G2 block abrogation sensitises human tumour cells for cytotoxins. Here we assess whether the chemosensitivity of prostate tumour cell lines can be enhanced by the application of a low dose of drug in conjunction with a G2 block abrogator. Prostate cell lines DU145, BM1604 and LNCaP were irradiated with 7 Gy 60Co gamma-irradiation. A sub-toxic (2 mM) dose of pentoxifylline and a cytotoxic drug were added at maximum expression of the G2 cell cycle block and cell survival was determined by colony assay. Cisplatin, etoposide and vinblastine were tested at a toxic dose of 10% (TD10). In the TP53 mutant cell lines, DU145 and BM1604, dose enhancement factors (EFs) were found to be in the region of 4.20 for cisplatin, 3.70 for vinblastine, and 3.20 for etoposide. In the TP53 wild-type cell line, LNCaP, the enhancement factors were low and in the region of 1.20 for cisplatin, vinblastine and etoposide. It is clear, therefore, that toxicity enhancement factors (EFs) are greater in the TP53 mutant cell lines, DU145 and BM1604, than in the TP53 wild-type cell line, LNCaP. The results indicate that a significant enhancement of drug toxicity can be obtained if the cytotoxic drug is given under conditions of G2 block abrogation. The sensitisation of prostate cancer cells to cytotoxic drugs is particularly high in radiation-resistant TP53 mutant tumour cells. Drugs which abrogate G2 block have the potential to enhance the therapeutic index and therefore reduce the toxicity of chemotherapy drugs.
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PMID:Chemosensitivity of prostatic tumour cell lines under conditions of G2 block abrogation. 1148 51

In several recent studies, we have shown that silibinin inhibits the growth of human prostate cancer cells (PCA) both in vitro and in vivo. Here, we investigated the effect of silibinin in combination with cisplatin and carboplatin on human PCA DU145 cell growth and apoptosis. Cisplatin alone at 2 microg/ml dose produced 48% cell growth inhibition, whereas a combination with 50-100 microM silibinin resulted in 63-80% (p<0.05-0.001) growth inhibition. Similarly, compared to 68% growth inhibition at 20 microg/ml carboplatin, addition of 50-100 microM doses of silibinin caused 80-90% inhibition (p<0.005-0.001). In the studies assessing the effect of these combinations on cell cycle progression, a combination of cisplatin or carboplatin with silibinin resulted in a stronger G2-M arrest, compared to these agents alone showing a moderate G2-M and G1 arrests in case of cisplatin and silibinin, and a complete S phase arrest with carboplatin, respectively. A stronger G2-M arrest by these combinations was accompanied by a substantial decrease in the levels of cdc2, cyclin B1 and cdc25C. Silibinin/platinum compound combinations were also effective in inducing apoptosis where cisplatin and carboplatin when combined with silibinin enhanced apoptosis from 8 to 15% and from 20 to 40%, respectively. Apoptosis induction was further confirmed by PARP and caspases 3, 9 and 7 whose cleaved levels were also enhanced by combination treatment. In addition, there was a significant increase in cytochrome c release in the cytosol following treatment of DU145 cells with these combinations. Together, these results show a substantial increase in the efficacy of platinum compounds on human PCA cells, when combined with silibinin, which provide a rationale for further investigations with these combinations.
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PMID:Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death. 1286 29

Acquired multi-drug resistance remains a major obstacle in the management of prostate cancer. The objective of this study was to examine whether chemoresistance could be due in part to the expression of the inhibitors of apoptosis proteins (IAPs). We established cisplatin-resistant LNCaP sublines. We examined the effects of cisplatin on cell growth and apoptosis in LNCaP cells and LNCaP sublines by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-1) assay and Hoechst 33258 staining, and analyzed cross-resistance to adriamycin, 5-fluorouracil, taxol, taxotere, and etoposide. In addition, the expression of IAP-1, IAP-2, X-linked IAP (XIAP), neuronal apoptosis inhibitory protein, and survivin was investigated by immunoblot analysis in LNCaP sublines. Although the growth rates were reduced in a dose-dependent manner by cisplatin in LNCaP sublines, the anti-proliferative effects of cisplatin were significantly decreased in LNCaP sublines compared to LNCaP cells. Cisplatin-resistant sublines, LNCaP/C1, LNCaP/ C2, and LNCaP/C3 cells, were 6.3-, 9.1-, and 22.3-fold more resistant to cisplatin than LNCaP cells, respectively, and this resistance was paralleled with reduced induction of apoptosis. LNCaP/C3 cells showed cross-resistance to adriamycin, 5-fluorouracil, and etoposide whereas those cells exhibited no or only weak cross-resistance against taxol and taxotere. With the exception of survivin, all the IAPs were identified in LNCaP cells by immunoblot analysis. Interestingly, the expression of IAP-2, XIAP, and survivin gradually increased with the extent of cisplatin-resistance. Altered expression of IAP-2, XIAP, and survivin was involved in these phenotypes of cisplatin-resistant LNCaP sublines. IAPs may make an important contribution to the resistance to the apoptotic effect of cisplatin in prostate cancer.
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PMID:Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells. 1614 63

Satraplatin is an orally bioavailable platinum analog that has activity in prostate cancer. JM118 is the most abundant species found in the plasma following the oral ingestion of satraplatin and has anti-tumor activity in vitro against cell lines that are resistant to cisplatin (DDP). The goal of the current study was to determine whether the activity of JM118 in some DDP-resistant cells can be explained by differences in the cellular pharmacology of the two drugs. The effect of each of the Cu transporters CTR1, ATP7A and ATP7B on sensitivity to the growth inhibitory effect of JM118 and its cellular pharmacology was examined to identify the characteristics of JM118 that distinguish it from DDP. These studies were performed using wild type and CTR1-/- homozygous knockout mouse embryo cells, and human Me32a Menkes disease fibroblasts that do not express either ATP7A or ATP7B plus sublines molecularly engineered to express either ATP7A (MeMNK cells) or ATP7B (MeWND cells). Knockout of the Cu influx transporter CTR1 in murine embryo cells increased their resistance to DDP and reduced its cellular accumulation but had no effect on sensitivity to JM118 or its uptake. In the case of DDP, forced expression of either of the two Cu efflux transporters, ATP7A or ATP7B, in Me32a cells rendered them resistant to DDP, increased whole cell accumulation of Pt but reduced the amount of Pt in DNA. In the case of JM118, forced expression of either ATP7A or ATP7B rendered Me32a cells resistant, increased not only whole cell Pt accumulation but also increased rather than decreased the amount of Pt in DNA. These results demonstrate that both ATP7A and ATP7B mediate resistance to JM118 as well as DDP and suggest that they sequester both DDP and JM118 into vesicular compartments within the cell resulting in enhanced whole cell accumulation and reduced cytotoxicity. We conclude that there are two important differences between DDP and JM118 with respect to the effect of Cu transporters on their cellular pharmacology. First, whereas CTR1 is involved in DDP accumulation it does not play a role in the uptake of JM118. Second, ATP7A and ATP7B, while they both mediate resistance, have opposite effects on the accumulation of Pt in DNA following exposure to the two drugs. ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in DNA following exposure to JM118. These results suggest that JM118 will retain activity in cells in which DDP resistance is due to the loss of CTR1, but not in cells in which resistance is due to enhanced expression of ATP7A or ATP7B.
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PMID:Modulation of the cellular pharmacology of JM118, the major metabolite of satraplatin, by copper influx and efflux transporters. 1617 May 71

DNA microarrays of promoter sequences have been developed in order to identify the profile of genes bound and activated by DNA regulatory proteins such as the transcription factors c-Jun and ATF2 as well as DNA-modifying methylases. The arrays contain 3083 unique human promoter sequences from +500 to -1000 nts from the transcription start site. Cisplatin-induced DNA damage rapidly leads to specific activation of the Jun kinase pathway leading to increased phosphorylation of c-Jun and ATF2-DNA complexes at hundreds of sites within 3 hours. Using three statistical criteria, approximately 269 most commonly phosphorylated c-Jun/ATF2-DNA complexes were identified and representative cases were verified by qPCR measurement of ChIP-captured DNA. Expression was correlated at the mRNA and protein levels. The largest functional cohort was 24 genes of known DNA repair function, most of which exhibited increased protein expression indicated coordinate gene regulation. In addition, cell lines of prostate cancer exhibit stable methylation or copy number changes that reflect the alterations of the corresponding primary tumors. 504 (18.5%) promoters showed differential hybridization between immortalized control prostate epithelial and cancer cell lines. Among candidate hypermethylated genes in cancer-derived lines, eight had previously been observed in prostate cancer, and 13 were previously determined methylation targets in other cancers. The vast majority of genes that appear to be both differentially methylated and differentially regulated between prostate epithelial and cancer cell lines are novel methylation targets, including PAK6, RAD50, TLX3, PIR51, MAP2K5, INSR, FBN1, GG2-1, representing a rich new source of candidate genes to study the role of DNA methylation in prostate tumors. Earlier studies using prototype promoter arrays examine approximately 7% of the proximal regulatory sequences while the current gene regulatory events surveyed here occur on a large scale and may rapidly effect the coordinated expression of a large number of genes.
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PMID:"Promoter array" studies identify cohorts of genes directly regulated by methylation, copy number change, or transcription factor binding in human cancer cells. 1639 35


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