Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of platinum compounds have been synthesized and screened on the basis of structure-activity strategy. In Japan, clinical trials of three analogues (NK-121, DWA-2114R and 254-S) have been undertaken. NK-121, which have the same leaving group as carboplatin, the dose limiting factor (DLF) was leukopenia, while renal toxicity was extremely mild. DWA-2114R, also with the same leaving group, was less nephrotoxic than CDDP or less marrow toxic than CBDCA. DLF was also leukopenia. Phase II study revealed 29% and 12% response rates for small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC), respectively. In 254-S which has the same carrier ligand (NH2) as CDDP and CBDCA. DLF was thrombocytopenia with mild nephrotoxicity. Response rates of 41% and 21% were obtained for SCLC and NSCLC, respectively. In a randomized study comparing 254-S plus VDS with CDDP plus VDS, equivalent response rate and milder toxicity were observed for the 254-S group. Since highly active agents other than platinum compounds have been currently evaluated for the cases of lung cancer, preclinical screening for substantially active compounds is essential in developing new platinum analogues.
 ...
PMID:[Development of platinum analogues for the treatment of lung cancer]. 133 25

I have established human lung squamous-carcinoma cell lines resistant to cis-Diamminedichloroplatinum (II) (CDDP), designated PC10-B3 and PC10-E5, from the original cell line PC10, by a stepwise increment of CDDP concentration. An MMT assay revealed that PC10-B3 was 11.4-fold, and PC10-E5 was 19.9-fold more resistant to CDDP than PC10, respectively. PC10-B3 was cross-resistant to CBDCA and 254-S, but not to doxorubicin and etoposide. The level of intracellular platinum accumulation was reduced by about 5 to 8-fold in PC10-B3 when compared with PC10. A two-dimensional gel electrophoresis was used to analyse the relative amount of proteins as between PC10 and its CDDP resistant sublines. The protein spot MW50 kD, pI5.3 was markedly reduced, and the spot MW50kD, pI4.9 was increased in PC10-B3 and PC10-E5 when compared to PC10. The spot MW58kD, pI5.8 newly appeared only in PC10-E5. I collected the most dramatically changed spot, MW50kD, pI5.3 (50kD-5.3), and processed it to determine its peptide sequence. I found that 50kD-5.3 was identical to 50kD, type I keratin (K14). Moreover, a retinoic acid-mediated K14 reduction was concomitant with a 4.0-fold transient increase in CDDP resistance in PC10. Taken together, the reduced intracellular platinum accumulation and the marked decrease of K14 imply that they are important factors in contributing to CDDP resistance in PC10-B3.
 ...
PMID:[Establishment and characterization of human lung squamous-carcinoma sublines resistant to cis-diamminedichloroplatinum (II)]. 142 97

In vitro and clinical data suggest that cisplatin and carboplatin resistance may be overcome in some cases by dose escalation, although clinical toxicities limit this approach. Administration of platinum analogues in combination is an alternative dose-intensification strategy that has been little studied. The cytotoxicities of cisplatin (CDDP), carboplatin (CBDCA), and tetraplatin (TP, ormaplatin) alone and in combination were assayed by inhibition of the clonogenic survival of human ovarian-carcinoma cell lines (a) from an untreated patient (A2780), (b) selected for CDDP resistance in vitro (2780-CP70), and (c) from patients presenting with clinically refractory disease (OVCAR3, OVCAR10). The sensitivity patterns of these cell lines to platinum analogues were consistent with the existence of at least two platinum-resistance phenotypes - one being moderately resistant to CDDP and CBDCA but highly resistant to TP and the other being highly resistant to CDDP and CBDCA but only partially cross-resistant with TP. Effects of drug combinations were determined by median-effect analysis. Interactions between platinum analogues were variable in different cell lines. Synergistic cytotoxicity was apparent for the CDDP-CBDCA combination in the A2780 and OVCAR-3 cell lines and for the CDDP-TP combination in 2780-CP70 and OVCAR-3. Strong antagonistic effects were seen for CBDCA-TP in 2780-CP70. Platinum analogues showed additive effects in the remaining cell lines. These data suggest that there may be distinct sensitivity phenotypes for platinum-analogue combinations. The demonstration of in vitro synergy between platinum analogues supports their combined clinical use.
 ...
PMID:In vitro interactions between platinum analogues in human ovarian-carcinoma cell lines. 156 85

A human lung squamous-carcinoma cell line resistant to cis-diamminedichloroplatinum(II) (CDDP), designated PC10-B3, has been established from the original cell line PC10 by a stepwise increment of the CDDP concentration. This is the first report, to our knowledge, to establish a CDDP-resistant lung squamous-carcinoma cell line. PC10-B3 has continued to proliferate in the presence of 0.5 micrograms/mL CDDP, whereas PC10 could not survive. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that PC10-B3 was 11.4-fold more resistant to CDDP than PC10 and cross-resistant to diammine(1,1-cyclobutanecarboxylate)platinum(II) (CBDCA) and 254-S, but not to doxorubicin or etoposide. PC10-B3 was characterized by a smaller DNA index and a larger cell size compared to PC10. The level of intracellular platinum accumulation was reduced by about 5- to 8-fold in PC10-B3 when compared with PC10, suggesting that reduced drug accumulation may be one of the important factors in contributing to CDDP resistance in PC10-B3.
 ...
PMID:Reduced drug accumulation in a newly established human lung squamous-carcinoma cell line resistant to cis-diamminedichloroplatinum(II). 164 51

In this phase I study, 16 adult cancer patients were treated with concurrent 4-day continuous infusions of ifosfamide at 12 g/m2 and escalating doses of carboplatin (400-1600 mg/m2) to determine the major non-haematological dose-limiting toxicity of the combination. Mesna was given by continuous infusion over 5 days for uroprotection (total dose per course = 15 g/m2). Autologous bone marrow support, which was mandated for subsequent dose levels once granulocytes remained below 500/microliters for more than 14 days in at least 2 patients entered at a given dose level, was used at dose levels above 400 mg/m2 carboplatin. Renal toxicity became dose-limiting at the maximum tolerated dose level of 1600 mg/m2 carboplatin. Temporary creatinine elevations above 2 mg/dl (median peak 2.6 mg/dl) were observed in 3 and irreversible renal toxicity occurred in 1 (peak creatinine 6.9 mg/dl, chronic creatinine 5-6 mg/dl) of the 5 patients entered at this dose level. Severe confusion and lethargy associated with rising creatinine developed in 2 patients. Two complete and four partial responses were documented in 14 heavily pretreated evaluable patients. The complete responses continue at 14+ and 20+ months in a patient with germ cell carcinoma and Ewing's sarcoma, respectively. Carboplatin appears to contribute to the renal toxicity of ifosfamide. Nevertheless, the combination of carboplatin and ifosfamide at 80% and 75% of the single-agent maximal tolerated doses respectively produced acceptable non-haematological toxicity. Further studies in the treatment of sarcoma, germ cell, ovarian and lung carcinomas with this combination are warranted.
 ...
PMID:Escalating doses of carboplatin with high-dose ifosfamide using autologous bone marrow as support: a phase I study. 179 9

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.
 ...
PMID:A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support. 184 7

We have studied the cellular pharmacokinetics of carboplatin (CBDCA), as part of the evaluation of the antitumor activity of CBDCA in cancers limited to the peritoneal cavity in comparison with cisplatin (cDDP). The uptake of CBDCA into L1210 (lymphosarcoma), CC531 (colonic carcinoma), COV413.B (human ovarian carcinoma) and NB1 (human neuroblastoma) cells was 1.5 to 13 times lower than the uptake of cDDP. The uptake of CBDCA into human ovarian carcinoma cells, taken directly from patients, was also 8-20 times lower than cDDP. Platinum concentrations, expressed as a percentage of the total intracellular Pt concentration, were similar for CBDCA and cDDP in cytosol and nucleus/membrane fractions. A second major difference between the drugs was their binding to DNA. Less CBDCA-DNA than cDDP-DNA adducts were formed after incubation at equimolar amounts of drug with isolated salmon sperm DNA (5-25 times less). A 16-69 times higher concentration of CBDCA than cDDP was needed to induce similar changes in cell growth activity (50% [3H]thymidine inhibition) in CC531 and COV413.B cells, indicating that equitoxicity can only be achieved when tumor cells are exposed to higher concentrations of CBDCA than cDDP. Similar toxicity was achieved in CC531 cells after incubation with a 16-fold higher CBDCA dose than cDDP. Comparable intracellular platinum concentrations, however, were obtained with a 10-fold higher CBDCA dose, suggesting that cellular pharmacokinetics of the drugs are different. Regarding drug uptake and pharmacokinetics the mechanism of action of CBDCA differed from cDDP at a cellular level.
 ...
PMID:Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action. 185 50

The closed relationship between nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV) has been pointed out. However, it still remains unclear whether the EBV becomes a true factor in initiation and promotion in NPC or not, because of difficulty to establish this cancer strain. We succeeded to establish the EBV-genome positive cell line (NPC-TY861) in 1986, which had been derived from the tissues of nasopharyngeal carcinoma. In this study, the characteristics of this cell strain were investigated by tests for sensitivity against several kinds of anti-cancerous agents and immuno-activated cells. The sensitivity tests revealed that NPC-TY861 cell line was extremely sensitive to PEP, ADR, VCR, LPA and CDDP with dose dependent manner. Furthermore, this cell strain had similar sensitivity to CDDP derivatives, such as 254-S, NK121, DWA2114R and CBDCA as KB cell strain did, which had been derived from an oral base cancer. The oral base cancer was a poorly differentiated squamous cell carcinoma histopathologically as same as NPC-TY861 cell strain. On the other hand, NPC-TY861 cell strain showed no sensitivity to cytokines, TNF and IFN, which have direct anti-cancerous actions. NPC-TY861 cell strain had resistant to NK cells and much more resistant to LAK cells derived from IL-2 than Daudi cell strain did. In order to elucidate the oncogeneous mechanism in NPC, it is indispensable to study the character of this cell strain and it would promise to get a new effective therapeutic method for the patient with NPC, who has bad prognosis.
 ...
PMID:[The characteristics of nasopharyngeal carcinoma cell strain against chemotherapeutic agents and cytokines]. 190 54

We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agent cytotoxicity and may be a clinically useful adjunctive therapy with these drugs.
 ...
PMID:Lonidamine as a modulator of alkylating agent activity in vitro and in vivo. 198 17

Cisplatin and 5-fluorouracil by continuous infusion combination produces a high response rate in squamous-cell carcinoma of the head and neck (SCCHN). Carboplatin (CBDCA) is a cisplatin analogue with lower emetic potential and nephrotoxicity, although the myelosuppression potential is higher. Tegafur (ftorafur, FT) is an analogue of 5-fluorouracil. It is absorbed well in its oral form and has moderate gastrointestinal and hematologic toxicity. This clinical trial tested the association of CBDCA i.v. plus FT p.o. in patients with SCCHN who had not been previously treated. Twenty-one patients were evaluable for response; the overall response was 62% (33% complete response, 29% partial response). Toxicity was moderate in most of the patients, although there was a treatment-related death.
 ...
PMID:Phase II trial of carboplatin and tegafur (Ftorafur) as induction therapy in squamous-cell carcinoma of the head and neck. 211 84


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