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It is known that some cancers show platinum complex resistance and that others show platinum complex sensitivity among ovarian cancers. Oxaliplatin (cis-[oxalato[trans-l-1, 2-diamino-cyclohexane] platinum[II]]; l-OHP), an active anti-cancer agent consisting of platinum, inhibits RNA synthesis and results in cytostatic effects. We investigated the difference between an oxaliplatin-resistant ovarian cancer cell line, KFR, and an oxaliplatin-sensitive ovarian cancer cell line, KF-1, using DNA microarray analysis. The oxaliplatin-resistant cell line, KFR, was established by using KF-1 cells derived from human serous cystadenocarcinoma of the ovary. Acquisition of platinum resistance in human ovarian cancer cells thus appeared to be related mainly to the expression of gamma-glutamylcysteine synthetase (gamma-GCS), topo II and metallothionein (hMT) genes, and partly to that of topo I and glutathione S-transferase--pi (GST-pi) genes, in addition to a decrease in platinum accumulation. KFR cells had 8.5- and 24.7-fold higher mRNA levels of gamma-glutamylcysteine synthetase (gamma-GCS), and topo II genes than KF-1 cells, while KFR had only a slight increase in the glutathione S-transferase--pi (GST-pi) mRNA level as compared with KF-1. In comparison of the gene expressions between KFR and KF-1 ovarian cancer cell lines, tubulin-specific chaperone E (TBCE) and CBP/p300-interacting transactivator (CITED2) were overexpressed in KFR compared to KF-1. These genes are overexpressed in MKN74, an oxaliplatin-resistant gastric cancer cell line, compared to MKN28, an oxaliplatin-sensitive gastric cancer cell line. TBCE is 13-fold increased in KFR cells compared to KF-1 cells. CBP/p300-interacting transactivator is increased 2-fold in KFR cells compared to KF-1 cells. The siRNA directed to the TBCE gene and CBP/p300-interacting transactivator gene enhanced the cytotoxicity of diplatin to the platinum-resistant ovarian cancer cell line KFR. These results show that the TBCE gene and CBP/p300 gene have potential as multidrug-resistant genes. It is necessary to check the effect of siRNA to influx or exflux. It has potential to enhance the effect of anti-cancer agents to resistant cancer cells, so we will proceed to develop an inhibitor of these TBCE and CBP/p300 proteins.

Oxaliplatin (trans-L-diaminocyclohexane oxalatoplatinum, L-OHP) is a novel cisplatin derivative that can improve the side effects of cisplatin such as toxicity to the kidneys and peripheral nerve system. However, L-OHP is effective only when combined with 5-Fluorouracil (5-FU) and Leucovorin. The relatively low anti-tumor index of L-OHP alone is because low levels accumulate in tumor tissues due to high partitioning to erythrocytes in vivo. A successful outcome of cancer therapy using L-OHP requires the selective delivery of a relatively high concentration of the drug to tumors. The present study examines tumor-selective delivery of L-OHP using liposomes modified with transferrin-conjugated polyethyleneglycol (TF-PEG-liposomes). Delivery using these liposomes significantly reduced L-OHP partitioning to erythrocytes and improved the circulation time of L-OHP in vivo, resulting in enhanced extravasation of liposomes into tumors. The TF-PEG-liposomes maintained a high L-OHP concentration in tumors for over 72 h after intravenous injection, which was longer than that of the liposomes modified with PEG (PEG-liposomes). Intravenously administered L-OHP encapsulated within TF-PEG-liposomes (L-OHP: 5 mg/kg) suppressed tumor growth more effectively than PEG-liposomes, Bare-liposomes and free L-OHP. Although L-OHP is usually combined with 5-FU and Leucovorin, our results suggest that L-OHP encapsulated within TF-PEG-liposomes has potential for cancer therapy.

A new dinuclear docking Pt(II) complex, (cis-diammine) (l-1,2-cyclohexanediamine)(mu-dichloro)-diplatinum(II) oxalate was synthesized by reacting oxaliplatin(l-OHP, [Pt(oxalato)(L-dach)]), L-dach = 1R, 2R-cyclohexanediamine), with cisplatin (CDDP). Elemental analysis of the compound indicated that it was 1:1 molar ratio complex of oxaliplatin and cisplatin. A plausible chemical structure has been proposed as Cl(-) bridged dinuclear complex, judged from its yellow coloration and NMR spectral analysis. This complex can be denoted as, i.e. [Pt(2)Cl(2)(NH(3))(2)(L-dach)](COO)(2) (L-OHP/CDDP). The complex showed higher cytotoxicity against L1210 than the parent complexes and low cross-resistance against L1210/CDDP and L1210/DACH. Its antitumor activity was also tested in vivo against murine leukemia L1210 cell lines. The complex showed much higher activity than the mixture(1:1 molar ratio) of oxaliplatin and cisplatin. The antitumor effect against L1210/CDDP was very high, showing collateral sensitivity, being similar to that of oxaliplatin, and against L1210/DACH it showed no cross-resistance.

We report that preoperative administration of Oxaliplatin, a new anti-cancer platinum agent, is an effective treatment for gastric cancer. The purpose of this in vitro study is to determine whether Oxaliplatin induces apoptosis in established human gastric cancer cell lines. Five established gastric cancer cell lines are used: MNK45, KATO-III, OKAJIMA, MNK28 and MNK74. Chemosensitivity to l-OHP is studied using a growth inhibition test. Induction of apoptosis in gastric cancer cells is analyzed by assessing DNA ladder formation, DNA fragmentation and actin cleavage. While all five gastric cancer cell lines are sensitive to Oxaliplatin, the poorly differentiated lines are the most sensitive. DNA ladder formation and/or DNA fragmentation are detected in all gastric cancer cell lines. However, actin cleavage is not detected in any of the cell lines. Oxaliplatin has an anti-cancer effect on human gastric cancer cell lines, particularly cell lines of poorly differentiated adenocarcinoma, indicating that Oxaliplatin would be an effective treatment for poorly differentiated gastric cancer. Oxaliplatin induces apoptosis in gastric cancer cell lines, but actin cleavage is not detected in cancer cells. This finding suggests that (1) the apoptotic caspase pathway leads mainly to DNA condensation and fragmentation, and (2) caspase-independent apoptotic pathways may be activated when gastric cancer cells are treated with Oxaliplatin.

A new lipophilic platinum (Pt) compound, trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)Pt(lV) (C5-OHP), was compared with cisplatin (CDDP) by intraperitoneal injection for antitumor activities against 3 different mouse models, L1210 leukemia, LMFS sarcoma with high metastatic potential and spontaneous mammary tumor. C5-OHP cured both CDDP-sensitive and -resistant L1210 leukemia frequently. CDDP did not cure the leukemia, although it prolonged the survival of diseased mice significantly. C5-OHP cured early and advanced LMFS sarcomas more frequently than CDDP. Cured mice had acquired antitumor immunity, indicating the pivotal role of the immune system in induction of the cure of tumors. It is likely tllat C5-OHP can eradicate tumor cells more effectively than CDDP by virtue of its weaker suppressive effects on the immune system. C5-OHP but not CDDP could cure mammary tumors. C5-OHP manifested a curative effect against LMFS tumors by oral route. These results indicate that C5-OHP is a promising anticancer agent worthy of clinical trial.

Purpose: The authors have previously reported that trans-bis(n-valerato)(1R,2R-cyclohexanediamine) (oxalato)platinum(IV) (C5-OHP), an oxaliplatin derivative, is an orally active antitumor agent in an intraperitoneal (i.p.) L1210 murine leukemia model. In this study, several oxaliplatin derivatives of the general formula trans-(carboxylato)chloro(1R,2R-cyclohexanediamine)(oxala to)platinum(IV) were synthesized in order to find new derivatives with greater oral activity than C5-OHP in a clinically predictive tumor model. In the formula, the carboxylate and chloride ligands are situated in axial positions., Method: Four complexes with the axial carboxylate ligands n-butyrate, n-valerate, n-caproate or n-heptanoate were synthesized and designated C4-OHP-Cl, C5-OHP-Cl, C6-OHP-Cl and C7-OHP-Cl, respectively. The oral antitumor activity of the complexes was evaluated against the murine reticulosarcoma M5076 implanted subcutaneoulsy (s.c.) in to male BDF1 mice. The complexes were administered orally daily for 5 days in two cycles initiated on days 5 and 12 postimplantation. The physicochemical properties were examined by measuring the concentrations of the complexes in test solutions at intervals by HPLC. The pharmacokinetic behaviors of C5-OHP-Cl, C6-OHP-Cl and C5-OHP following a single oral administration were studied in non-tumor-bearing male BDFl mice., Results: Of the complexes synthesized in this study, C5-OHP-Cl, which exhibited high activity in the i.p. L1210 model, was found to be orally active in the s.c. M5076 model while C5-OHP was not. The in vitro reduction of the complexes by ascorbate was much more rapid than that of C5-OHP, while the complexes were more stable than C5-OHP in HCl-acidic and alkaline solutions. Pharmacokinetic study showed that Cmax and AUC0 24h values of plasma total and filterable platinum of C5-OHP-Cl were four to six times greater than those of C5-OHP, indicating that C5-OHP-Cl was absorbed more than C5-OHP., Conclusion: C5-OHP-Cl was found to be a superior 1-OHP derivative C5-OHP, exhibiting significant oral antitumor activity in the s.c. M5076 model. The enhanced activity of C5-OHP-Cl was considered to be due in part to increased susceptibility to reduction and increased gastrointestinal absorption. C5-OHP-Cl is a suitable candidate for further study as an oral cancer chemotherapy agent.

Trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato++ +)platinum(IV) (C5-OHP) is an orally active platinum complex we prepared. The gastrointestinal absorption of C5-OHP was examined in rats and compared with those of C5-OHP analogs which have a general formula of trans-bis(n-OCOCnH2n+1)(1R,2R-cyclohexanediamine)(oxalato )platinum(IV) as well as C5-OHP. The complexes did not show significant differences in pharmacokinetic behavior after i.v. injection. Plasma platinum level after a single oral administration at a dose was higher for a complex with higher water solubility. The intestinal absorption rate measured by an in situ recirculating perfusion technique was higher for a complex with higher lipophilicity. These results indicate that the water solubility is a more dominant factor than the lipophilicity in the gastrointestinal absorption of the complexes. Then, the effects of surfactants and alpha-cyclodextrin (alpha-CD) on the solubility of C5-OHP was studied. Among the agents tested, alpha-CD showed the highest effect in increasing the solubility. Administration of C5-OHP together with alpha-CD gave approximately three times higher plasma platinum levels than administration of C5-OHP alone. Water solubility was found to be a dominant factor in the gastrointestinal absorption of C5-OHP and its analogs.

A new DACH platinum complex, l-OHP, was developed by Kidani as an anticancer agent. A clinical trial took place in Europe which demonstrated its therapeutic efficacy for colorectal cancer. An effective treatment, especially chemotherapy for patients with a advanced scirrhous type gastric cancer, has not yet been established. An in vitro study showed that l-HOP inhibited cell growth in human gastric cancer cell lines. Our pilot study determined the efficacy of preoperative administration of l-OHP, 67 mg/m2 to 100 mg/m2, every 2-3 weeks, for two to three cycles, in five patients with this disease (Stage III and IV) roentogenoscopically and histologically. The platinum concentration in the tissues was also measured. By X-ray examination of the stomach at the time of pre- and post-administration of l-OHP, extension of the lesional gastric wall was observed. Histologically three Grade 2 responses and two Grade 1a responses were obtained according to the criteria presented by Japanese Research Society for Gastric Cancer. The mean platinum concentrations in the lesional tissues were 0.98 ppm and 0.5 ppm in the patients administered l-OHP for three and two cycles respectively. There was no toxicity that prevented surgery. These preliminary results showed the possibility that 1-OHP would be effective for patients with advanced scirrhous type gastric cancer as a neoadjuvant therapy.

In order to develop orally active antitumor platinum complexes, several cyclohexanediamine-Pt(IV) complexes of a general formula trans,cis,cis-[Pt(IV) (OCOCnHn+1)2 (oxalato)(1R,2R-cyclohexanediamine)] were synthesized by derivatizing oxaliplatin [Pt(II)(oxalato)(1R,2R-cyclohexanediamine), I-OHP], which is a potent antitumor cyclohexanediamine-Pt(II) complex we have prepared and now undergoing clinical trials. The I-OHP derivatives were found to be stable, lipophilic and reduced to yield I-OHP, an active species, quantitatively by ascorbate in vitro. All the derivatives were antitumor active against mouse lymphocytic leukemia L1210 when given i.p. In particular, trans-bis-valerato-oxalato-1R,2R-dach-Pt(IV), C5-OHP, showed markedly high activity. C5-OHP also exhibited significant antitumor activity against L1210 when orally administered. C5-OHP was considered to be a suitable candidate for the oral cancer chemotherapy agent to be developed.

A new platinum complex, oxalatoplatin or l-OHP, which, at the same metal dose in experimental tests is as efficient as cisplatin, and is more so at a lower metal dose than carboplatin; which is as efficient in human tumors of the testis and ovary as these other analogs, and more so in melanoma and breast cancer; which is not nephrotoxic, cardiotoxic or mutagenic, and hardly hematotoxic and neurotoxic, is described and compared with the above-mentioned platinum complexes. Combined with 5Fu, it induces a high number of remissions in colorectal cancer, and has brought about cures in inoperable gastric cancers. Combined with carboplatin, it has resulted in a high proportion of cures in L1210-carrying mice, which no other two-by-two combination of these complexes has achieved.