-
British Journal of Cancer Apr 2003AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts.... (Clinical Trial)
Clinical Trial
AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.
Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Neoplasms; Organoplatinum Compounds
PubMed: 12671715
DOI: 10.1038/sj.bjc.6600854 -
International Journal of Cancer Sep 1998The P53 gene is frequently mutated in late stage ovarian cancer and has been proposed as a determinant of radiation and chemosensitivity. We have therefore determined...
The P53 gene is frequently mutated in late stage ovarian cancer and has been proposed as a determinant of radiation and chemosensitivity. We have therefore determined the p53 functional status, P53 sequence, radiation sensitivity and cytotoxicity of cisplatin and the novel platinum analogue, AMD473, in a panel of 6 human ovarian cancer cell lines. Constitutive p53 protein levels were low in A2780, CH1, LK1, LK2 and PA1 but were markedly induced following irradiation. In OV1P, constitutive p53 protein was readily detectable and levels were induced slightly following irradiation. p21WAF1/CIP1 and MDM-2 mRNA were constitutively expressed in all the cell lines and expression was induced markedly following irradiation. There was marked radiation induced G1/S arrest in A2780 but only partial arrests in CH1, LK1, LK2, PA1 and OV1P lines. No mutations were found in A2780, CH1, LK1, LK2 and PA1 cells by single-strand conformational polymorphism (SSCP) analysis but a heterozygous point mutation was found in exon 5 of OV1P. All the cell lines were radiation sensitive and also relatively sensitive to cisplatin; however, OV1P was the most resistant being consistent with its heterozygous P53 status. AMD473 was less potent than cisplatin but a similar pattern of drug sensitivity was observed with the exception of LK2, which was resistant. CH1, LK1, LK2 and PA1 all expressed BCL-2 protein but there was no expression in A2780 and OV1P. Our results suggest an overall association between wild type P53 and radiation and platinum drug sensitivity in these ovarian cancer cell lines.
Topics: Antineoplastic Agents; Blotting, Northern; Carcinoma; Cisplatin; DNA Primers; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Organoplatinum Compounds; Ovarian Neoplasms; Polymerase Chain Reaction; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 9714063
DOI: 10.1002/(sici)1097-0215(19980911)77:6<913::aid-ijc19>3.0.co;2-1 -
The American Journal of Pathology Jul 1999During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216,...
During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216, and the structurally hindered analogue AMD473, has been established and characterized for underlying mechanisms of resistance. We have examined these resistant cell lines for gains and losses of DNA associated with the acquisition of resistance using the molecular cytogenetic technique of comparative genomic hybridization. Our comparison of three analogues has shown the most frequently observed changes to include amplification of 4q (5/7) and 6q (5/7), followed by amplification of 5q (3/7). We have defined four minimal common overrepresented regions, two each on 4q and 6q, which are potential loci of genes associated with platinum analogue resistance. Additional consistent abnormalities appear to be associated with cell lines sharing specific resistance mechanisms. For example, amplification of 12q was observed in the CH1 lines made respectively resistant to JM216 and AMD473 in which increased DNA repair appears to be a major mechanism of resistance for both agents. Hence, these comparative genomic hybridization studies have identified distinct chromosomal aberrations which may correlate with defined mechanisms of resistance and contain hitherto unrecognized genes that may provide targets for future therapeutic intervention.
Topics: Antineoplastic Agents; Chromosome Aberrations; Chromosomes; Cisplatin; Drug Resistance, Neoplasm; Genome; Humans; Nucleic Acid Hybridization; Organoplatinum Compounds; Platinum; Tumor Cells, Cultured
PubMed: 10393840
DOI: 10.1016/S0002-9440(10)65102-4 -
Journal of the American Chemical Society Aug 2013Despite the broad use of platinum-based chemotherapeutics, identification of their full range of cellular targets remains a significant challenge. In order to identify,...
Despite the broad use of platinum-based chemotherapeutics, identification of their full range of cellular targets remains a significant challenge. In order to identify, visualize, and isolate cellular targets of Pt(II) complexes, we have modified the chemotherapeutic drug picoplatin with an azide moiety for subsequent click reactivity. The new compound picazoplatin readily binds DNA and RNA oligonucleotides and undergoes facile post-labeling click reactions to alkyne-fluorophore conjugates. Pt-fluorophore click reactions in rRNA purified from drug-treated Saccharomyces cerevisiae demonstrate its potential for future in vivo efforts.
Topics: Alkynes; Azides; Click Chemistry; Drug Discovery; Fluorescent Dyes; Models, Molecular; Oligonucleotides; Organoplatinum Compounds
PubMed: 23879391
DOI: 10.1021/ja402453k -
Anticancer Research 2004Three pairs of human tumour cell lines, with one line of each pair resistant to cisplatin, were used to compare the effects of cisplatin and ZD0473 on cellular toxicity... (Comparative Study)
Comparative Study
Three pairs of human tumour cell lines, with one line of each pair resistant to cisplatin, were used to compare the effects of cisplatin and ZD0473 on cellular toxicity and radiosensitization. Whilst all three cell line pairs had one line that was resistant to cisplatin, for ZD0473 the lung tumour HTB56cp and cervical carcinoma ME180 cell lines did not express resistance to their HTB56 and SHA counterparts, respectively. Only the ovarian carcinoma line A2780cp showed resistance to ZD0473 compared to its counterpart A2780S. For radiosensitization both cisplatin and ZD0473 show additive and subadditive effects in the ovarian carcinoma lines, and additive and superadditive effects in the cervical carcinoma and lung tumour cell lines. In fact in the lung tumour cell lines ZD0473 appeared to be a more effective radiosensitizer than cisplatin.
Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Neoplasms; Organoplatinum Compounds; Ovarian Neoplasms; Radiation-Sensitizing Agents; Uterine Cervical Neoplasms
PubMed: 15161002
DOI: No ID Found -
British Journal of Cancer Jul 1998The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their variants with acquired cisplatin...
The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their variants with acquired cisplatin resistance was determined using Western blotting. No overexpression of MRP1 was detected in any of the cell lines. In addition, we have transfected the MRP1 gene into an intrinsically cisplatin-resistant cell line SKOV3, previously shown to have elevated levels of glutathione (GSH). The MRP1-transfected line SKOV3-S2 was shown to be cross-resistant to doxorubicin, vincristine and etoposide but not to paclitaxel, vinblastine and platinum agents, such as cisplatin, JM216 [bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV)] and AMD473 [cis-ammine dichloro (2-methyl-pyridine) platinum (II)]. No cross-resistance to any of the platinum agents was observed in a MRP1-overexpressing human lung cancer cell line with acquired doxorubicin resistance. Reduction of GSH levels (80-90%) by buthionine sulphoximine (BSO) produced significant potentiation in cisplatin sensitivity in the parental SKOV3, the vector-alone control SKOV3-puro and the MRP1-transfected line SKOV3-S2. The degree of sensitization was similar in all cell lines (1.6-fold). However, selective sensitization by BSO to vincristine was observed in the MRP1-transfected line (4.1-fold) but not in the vector control. No significant differences were observed in cisplatin accumulation in the SKOV3-puro and the SKOV3-S2 cells, although both these transfected lines accumulated significantly more than the parental line. Our results suggest that MRP1 does not play a significant role in platinum resistance in the human tumour cell lines investigated in this study.
Topics: ATP-Binding Cassette Transporters; Antineoplastic Agents; Blotting, Western; Buthionine Sulfoximine; Cisplatin; Drug Resistance, Neoplasm; Female; Humans; Multidrug Resistance-Associated Proteins; Organoplatinum Compounds; Ovarian Neoplasms; Tumor Cells, Cultured; Vincristine
PubMed: 9683290
DOI: 10.1038/bjc.1998.461 -
Annals of Oncology : Official Journal... Apr 2003ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant... (Clinical Trial)
Clinical Trial
A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129.
BACKGROUND
ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group.
PATIENTS AND METHODS
Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m(2) every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m(2) on the basis of emergent data from studies ongoing at the time.
RESULTS
Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m(2) and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m(2). Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m(2) and two patients (10%) at 120 mg/m(2). Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients.
CONCLUSION
ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.
Topics: Adult; Aged; Breast Neoplasms; Disease Progression; Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Treatment Outcome
PubMed: 12649098
DOI: 10.1093/annonc/mdg171 -
British Journal of Cancer 1998A novel sterically hindered platinum complex, AMD473 [cis-aminedichloro(2-methylpyridine) platinum (II)], has been selected for phase I clinical trials due to commence...
A novel sterically hindered platinum complex, AMD473 [cis-aminedichloro(2-methylpyridine) platinum (II)], has been selected for phase I clinical trials due to commence in 1997. AMD473 was rationally designed to react preferentially with nucleic acids over sulphur ligands such as glutathione. This report documents the in vitro circumvention of acquired cisplatin resistance mechanisms in human ovarian carcinoma (HOC) cell lines by AMD473. In a panel of 11 HOC cell lines, AMD473 showed intermediate growth inhibition potency (mean IC50 of 8.1 microM) in comparison to cisplatin (mean IC50 of 2.6 microM) and carboplatin (mean IC50 of 20.3 microM). AMD473 showed only a 30.7-fold increase in IC50 value from the most sensitive to the most resistant HOC cell line, whereas for cisplatin it was 117.9-fold and for carboplatin 119.7-fold. AMD473 also showed significantly (P < 0.05) reduced cross-resistance to cisplatin in a panel of three cell lines with known acquired platinum drug resistance mechanisms (mean RF for AMD473 was 1.9, for cisplatin 9.1). Cellular accumulation of AMD473 was not reduced in two HOC cell lines (A2780cisR and 41McisR), in which reduced cisplatin accumulation is a major mechanism of acquired cisplatin resistance. AMD473 naked-DNA binding was significantly less affected (P < 0.05) than that of cisplatin by the presence of 5 mM glutathione. Also, AMD473 almost completely circumvented acquired cisplatin resistance in a cell line (A2780cisR) with fivefold elevated intracellular glutathione levels compared with the parent A2780 cell line when measured by clonogenic assay (RF 4.5 for AMD473 vs RF 18 for cisplatin). AMD473 also showed a lower increase in IC50 than cisplatin in an A2780 cell line model with artificially elevated glutathione levels. AMD473 DNA binding was slower than that of cisplatin on both naked and cellular DNA. AMD473 also formed DNA interstrand cross-links (ICLs) at a slower rate than cisplatin (peak ICL formation was at 5 h for cisplatin vs > or = 14 h for AMD473) after equitoxic doses were exposed to HOC cells for 2 h. AMD473 ICLs in the CH1 HOC cell line were slowly formed and showed no visible signs of being repaired 24 h after removal of drug. This was paralleled by a slower, longer lasting induction of p53 protein by equitoxic doses of AMD473 in HOC cell lines with wild-type p53. This new class of sterically hindered platinum compound, selected for clinical trial in 1997, may therefore elicit improved clinical response in intrinsically and acquired cisplatin-resistant tumours in the clinic.
Topics: Antineoplastic Agents; Cisplatin; DNA; Drug Resistance, Neoplasm; Glutathione; Humans; Organoplatinum Compounds; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 9472630
DOI: 10.1038/bjc.1998.59 -
Bulletin Du Cancer Jan 2003MGI114, ET743, BBR3464, ZD0473, ZD9331, BN80915, J107088, F11782, XR11576, BMS247550, PS341, UCN01, ISIS 3521, STI571, ZD1839, IMC-C225, OSI774, SU5416, DNA minor and...
MGI114, ET743, BBR3464, ZD0473, ZD9331, BN80915, J107088, F11782, XR11576, BMS247550, PS341, UCN01, ISIS 3521, STI571, ZD1839, IMC-C225, OSI774, SU5416, DNA minor and major grooves, chimeric proteins, ribonucleotide reductase, topoisomerases, tubuline, proteasome, protein kinase C, bcr-abl, EGF or VEGF tyrosine kinase receptors are code names (somewhat barbarian) and targets for new drugs which will complement the therapeutic arsenal of the twenty-first century oncologist. This review provides a survey their clinical advances.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Boronic Acids; Bortezomib; Dioxoles; Indoles; Isoquinolines; Neoplasms; Organoplatinum Compounds; Protease Inhibitors; Pyrazines; Pyrroles; Quinazolines; Sesquiterpenes; Tetrahydroisoquinolines; Trabectedin
PubMed: 12609801
DOI: No ID Found