Disease relevance of NCI60_000547

• The results confirm a role for beta-adrenergics in the management of experimental ADM skin ulceration and suggest that local toxicity is mediated through specific beta-receptors (possibly beta 1) in the mouse skin [1].
• PATIENTS AND METHODS: Seventy-one patients with stage IV breast cancer were treated with Caelyx at doses of 45 to 60 mg/m2 every 3 to 4 weeks for a maximum of six cycles [2].
• Radiation improves the distribution and uptake of liposomal doxorubicin (caelyx) in human osteosarcoma xenografts [3].
• Total cytosolic ACC activity, expressed per g body weight, was increased in both NA and ADR rats by 45% and 39%, respectively (P < 0.05) [4].
• Phase III data on Caelyx in ovarian cancer [5].

High impact information on NCI60_000547

• A dramatic stimulation of P-gp activity against Adr and Rho-123 by the identified compounds was accompanied by suppression of P-gp-mediated efflux of other substrates, such as Taxol (paclitaxel) or Hoechst 33342, indicating that they act as modulators of substrate specificity of P-gp [6].
• RESULTS: The maximum tolerated dose of Caelyx was 20 mg/m(2) for HNC and 25 mg/m(2) in NSCLC patients [7].
• PURPOSE: A multicenter phase II study to determine the activity and toxicity of Caelyx (Doxil; Sequus Pharmaceuticals Inc, Menlo Park, CA) in patients with metastatic breast cancer [2].
• Measurements of ADR uptake and efflux indicate that, unlike other multidrug resistance modifiers, valinomycin exerts its actions in modulating ADR resistance by mechanism(s) other than increasing intracellular accumulation of Adriamycin [8].
• By contrast, 4-HDC, Adriamycin (ADR), cisplatin (CDP), and methotrexate (MTX) had no effect on FasL mRNA expression [9].

Chemical compound and disease context of NCI60_000547

• It is concluded that the subcutaneous administration of amifostine during high dose Taxotere/Caelyx chemo-radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the 'in-field' toxicity to the levels expected from simple conventional radiotherapy [10].
• In conclusion, CAELYX has equivalent activity to doxorubicin in STS with an improved toxicity profile and should be considered for further investigation in combination with other agents such as ifosfamide [11].
• EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. European Organization for Research and Treatment of Cancer [12].
• Phase II study of pegylated liposomal doxorubicin HCl (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small cell lung cancer [13].
• Against colon adenocarcinoma 26, the PSC 833/ADM combinations induced cure in two or three of six mice [14].

Biological context of NCI60_000547

• Under the same assay conditions, ADR demonstrated much higher IC50 values: 550 microM for TPA and greater than 350 microM for PDBu [15].
• Amongst the factors governing the response of cells in spheroids to cytotoxic drugs, the responses to ADM and VCR are thought to be largely dictated by cell cycle distribution and limited drug penetrability, whilst for HN2 the response may be determined by the factor of cell cycle distribution [16].
• Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel [17].
• In contrast, X-ray-pretreated VCR-resistant cells (MCF/DXR-10) cells exhibited a distinctive resistance phenotype proving cross-resistant to VLB and VP-16 but not to ADR, and Pgp overexpression was not detectable [18].
• These preliminary data indicate a difference in biotransformation between ADR and 4'-DOX despite their close structural similarities [19].

Anatomical context of NCI60_000547

• AM, DEA and verapamil induced an increase in cytotoxicity of Adr, vincristine and etoposide (VP16) in COLO 320 cells, while in the GLC4 and GLC4-Adr cell line no effect was seen [20].
• The colony-forming unit granulocyte macrophage (CFU-GM) assay showed no increase in cytotoxicity of Adr when AM was added [20].
• Bone-marrow toxicity was the same as expected from Adr alone in these patients [20].
• Thus, we conclude that administration of ADR not mixed with lipiodol and given through the hepatic artery is the preferred modality for treating early metastatic liver tumors [21].
• In groups III and IV, ADR mixed with lipiodol (lipiodolized ADR) 4 mg/kg was given into the hepatic artery or into the portal vein, respectively, 24 h after inoculation [21].

Associations of NCI60_000547 with other chemical compounds

• Furthermore, an additive growth inhibitory effect occurred when GEO cells were exposed to the AS S-oligos after treatment with different concentrations of either 5-FU, MIT, ADR or CDDP [22].
• CDDP and ADR, which sensitized DU145 and PC-3 cells to Fas-L- and TNF-mediated killing, inhibited de novo protein synthesis in both cell lines, while VP-16 only inhibited protein synthesis in DU145 cells [23].
• For POC spheroids, cells in the outer region of spheroids are more sensitive to ADM and VCR than cells in the inner region whilst a reverse trend is seen for the response to CCNU [16].
• RESULTS: The drugs cis-diamminedichloroplatinum (II) (CDDP), adriamycin (ADR), and etoposide (VP-16) sensitized DU145 and PC-3 cells to Fas killing [23].
• This effect is discernible at significantly lower levels of AD 143 than of ADR, corresponding to less than LD50 measured by the clonogenic assay [24].

Gene context of NCI60_000547

• Also consistent with independence of P-170gp mediated MDR and TNF response, the P388/ADM cell line (exhibiting P-170gp mediated MDR) remained as resistant to TNF as the P388 parental line [25].
• Total FAS activity was increased by 65% and 115% in NA and ADR rats, respectively (P < 0.05) [4].
• Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2 [26].
• BACKGROUND: The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC) [27].
• The objective of this multicenter phase II study was to evaluate the safety, tolerance and anti-tumour activity of Caelyx as monotherapy in patients with recurrent SCLC [28].

Analytical, diagnostic and therapeutic context of NCI60_000547

• Caelyx was injected i.v. 1 day before single or fractionated radiotherapy [3].
• Improved RFS and OS were observed in the HER2+ subgroup after treatment with CMF plus ADM versus CMF alone [29].
• PURPOSE: This is the first study to evaluate the tolerability and activity of liposomal doxorubicin (Caelyx; Schering-Plough Pharmaceuticals) < or =60 mg/km(2) in patients with locally recurrent breast cancer, when administered in conjunction with reirradiation and local hyperthermia treatment [30].
• PATIENTS AND METHODS: Treatment consisted of escalating doses of Caelyx (12.5-17.5 mg/m2) administered as a 30-min intravenous infusion on day 1 and paclitaxel (90-115 mg/m2) as a 3-hour intravenous infusion on day 2 every 2 weeks without growth factor support [31].
• Phase II study of pegylated liposomal doxorubicin (Caelyx) as induction chemotherapy for patients with squamous cell cancer of the head and neck [32].

References