Preclinical in vivo antitumor efficacy of nedaplatin with gemcitabine against human lung cancer.

The antitumor efficacy of the combination of nedaplatin (NDP) with gemcitabine (GEM) was evaluated. We also compared the antitumor activity of NDP plus GEM with that of cisplatin (CDDP) plus GEM or carboplatin (CBDCA) plus GEM. Ma44, which is a human lung cancer sensitive to GEM, and NCI-H460, which is a human lung cancer refractory to GEM, were used in this study. GEM was injected i.v. once followed by i.v. injection of NDP at an interval of approximately 30 min into tumor-bearing athymic mice. GEM was administered again 3 or 4 days thereafter. Combined dosing of NDP with GEM resulted in synergistically enhanced inhibition of tumor growth in the Ma44 tumor model. NDP plus GEM was also effective against Ma44 cells when given late in the therapy, a model for advanced disease. Potent augmentation of growth inhibition by NDP with GEM was also found with the NCI-H460 tumor model. The combination effect of NDP plus GEM appeared to be superior to that of CDDP plus GEM or CBDCA plus GEM in both tumor models. Toxicity in terms of blood cell numbers was not enhanced by the combination of NDP with GEM. These results suggest the effectiveness of combination of NDP with GEM for clinical therapy.     

Combination chemotherapy with nedaplatin and cyclophosphamide in human ovarian cancer model.

The antitumor efficacy of the combination of nedaplatin (NDP) with cyclophosphamide (CPM) was evaluated using human ovarian cancer models. Since NDP has been found to have greater antitumor activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumor activity of NDP plus CPM with that of CDDP plus CPM. Increasing doses of NDP (16.5, 33 and 66 mg/kg as a total dose) and a fixed amount of CPM (174 or 348 mg/kg as a total dose) were injected three times at intervals of 7 days via the tail vein into mice implanted with RMUG-S, OC9-JCK or KF-28 human ovarian cancer. Simultaneous administration of NDP with CPM resulted in markedly enhanced inhibition of tumor growth for all cancers tested. The growth inhibition and survival effect of the combination therapy of NDP with CPM against KF-28 and OC9-JCK were as potent as those of CDDP plus CPM. Neither increased hematotoxicity nor a significant difference in maximum concentration, half time or area under the curve of platinum or CPM in plasma between the single and combined treatment was found. These results suggest that the combination of NDP with CPM may be clinically effective.     

Combination Chemotherapy with Nedaplatin and Cyclophosphamide in Human Ovarian Cancer Model

The antitumor efficacy of the combination of nedaplatin (NDP) with cyclophosphamide (CPM) was evaluated using human ovarian cancer models. Since NDP has been found to have greater anti-tumor activity and lower nephrotoxicity than cisplatin (CDDP), we also compared the antitumor activity of NDP plus CPM with that of CDDP plus CPM. Increasing doses of NDP (16.5, 33 and 66 mg/kg as a total dose) and a fixed amount of CPM (174 or 348 mg/kg as a total dose) were injected three times at intervals of 7 days via the tail vein into mice implanted with RMUG-S, OC9-JCK or KF-28 human ovarian cancer. Simultaneous administration of NDP with CPM resulted in markedly enhanced inhibition of tumor growth for all cancers tested. The growth inhibition and survival effect of the combination therapy of NDP with CPM against KF-28 and OC9-JCK were as potent as those of CDDP plus CPM. Neither increased hematotoxicity nor a significant difference in maximum concentration, half time or area under the curve of platinum or CPM in plasma between the single and combined treatment was found. These results suggest that the combination of NDP with CPM may be clinically effective.     

New regimens for the treatment of gynecologic cancers

Until the late-1980s, combination CDDP (or CBDCA)/cyclophosphamide (CPA) and CDDP (or CBDCA)/CPA/adriamycin (ADM) were the two most common choices for treating patients with ovarian cancer. In the last several years, the identification of paclitaxel (TXL) activity in previously treated ovarian cancer patients has led to its incorporation into primary chemotherapy regimens for newly diagnosed patients. Based on prospective trials by the Gynecologic Oncology Group (GOG) and European-Canadian investigators, CDDP/TXL became the new standard regimen in 1998. Now, three randomized trials by the GOG (158), AGO, and a Dutch group comparing CDDP/TXL and carboplatin (CBDCA)/TXL are also in progress. These study groups recommended that CBDCA/TXL be used as the standard regimen in 1999 because CBDCA/TXL is less toxic, allows a better quality of life during treatment, and results in an equivalent response rate and progression-free survival. In patients with high-risk corpus cancer, clinical trials comparing platinum/TXL or platinum/ADM/TXL versus platinum/ADM are in progress. In Japan, CPT-11/CDDP has been shown to be an effective and safe regimen in patients with advanced ovarian cancer, especially clear cell carcinoma and cervical cancer.     

A case of papillary adenocarcinoma of the ovary that responded favorably to irinotecan hydrochloride and cisplatin after the administration of paclitaxel and carboplatin]

Recently, the standard treatment for advanced ovarian cancer has changed from CP therapy (cyclophosphamide, cisplatin (CDDP)) to TJ therapy (paclitaxel (TXL), carboplatin (CBDCA)). Irinotecan (CPT-11) is one of the derivatives of camptotecin and has been reported to have a high efficacy for ovarian cancer. In one case of ovarian cancer, chemotherapy was applied with CBDCA and TXL. However, after 2 months of six courses of the chemotherapy, CA-125 was elevated. The elevation of tumor marker levels in serum without the recurrent focus forced us to treat the patient with CPT-11 and CDDP for the second line chemotherapy. Tumor marker levels improved at the beginning of the therapy. In conclusion, CPT-11 and CDDP was effective against the recurrence of ovarian cancer treated with TJ therapy.     

Refractory non-small-cell lung cancer responding to combination chemotherapy with docetaxel, gemcitabine and cisplatin

The combination of docetaxel (TXT), gemcitabine (GEM), and cisplatin (CDDP) produced a regression in a squamous cell carcinoma of the lung that had recurred after radiation therapy plus chemotherapy, and was resistant to the combination of carboplatin (CBDCA) with etoposide (ETP) or paclitaxel (TXL). The patient was a 62-year-old man with squamous cell lung cancer, which was first successfully treated by a combination of radiation therapy and chemotherapy, but showed local recurrence after 8 months. Although the recurrence was treated with CBDCA plus ETP and then TXL, the tumor continued to grow with symptomatic progression of airway stenosis. The tumor began to regress after the regimen of TXT, GEM and CDDP was started. This therapy achieved PR with symptomatic improvement. The combination of TXT, GEM and CDDP may be effective for recurrent non-small-cell lung carcinoma, even in patients that have failed to respond to more than one chemotherapy regimen.     

Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethy1)-2-isopropyl-1,3-dioxolanelplatinum(II), a new platinum analogue,as an anticancer agent

 The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4, 5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug. Received: 7 June 1994 / Accepted: 27 September 1994     

Advanced non-small cell lung cancer responded to both vinorelbine and carboplatin over long-term outpatient treatment

We treated a patient with lung adenocarcinoma who responded to chemotherapy with vinorelbine (VNR) plus carboplatin (CBDCA) on an outpatient basis. The patient was a 68-year-old man. He visited a local physician complaining of wet coughing, headache and general fatigne. The symptoms remained unchanged and the patient was admitted to our department for treatment in June 2000. A massive shadow in the right upper lobe and multiple cerebral metastases were found. Based on this, the diagnosis was lung adenocarcinoma (T3N2M1, clinical stage IV). Whole-brain irradiation and systemic chemotherapy were initiated from July 2000. The patient received 1 course of systemic chemotherapy with vindesine (VDS) plus cisplatin (CDDP) on an inpatient basis. This regimen was replaced with combination therapy of paclitaxel (TXL) plus CBDCA in the outpatient setting, along with VNR plus CBDCA due to side effects caused by TXL. The cerebral metastases almost disappeared due to whole-brain irradiation. Chest CT after 3 courses revealed a reduction in primary tumor size. The VNR plus CBDCA combination therapy was continued for a further 6 courses. As the result, neither the primary tumor nor the cerebral metastases enlarged. The combination therapy with VNR plus CBDCA seems to be a useful regimen that can maintain high QOL and be conducted for a long term on an outpatient basis.     

Increased therapeutic efficacy induced by tumor necrosis factor alpha combined with platinum complexes and whole-body hyperthermia in rats.

This study examined the effect of a trimodality therapy of the combination of recombinant human tumor necrosis factor alpha (TNF), whole-body hypertheria (WBH), and cis-diamminedichloroplatinum(II) (CDDP) or cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA) on a fibrosarcoma and normal tissue in F344 rats. TNF (1 x 10(5) units/kg) increased the antitumor effect of both CDDP (1.5 mg/kg) + WBH (2 h at 41.5 degrees C) and CBDCA (30 mg/kg) + WBH. Tumor growth delay, which was 1.9 days for CDDP + WBH and 2.7 days for CBDCA + WBH (P less than 0.01 compared to control), was significantly increased to 2.9 days with TNF + CDDP + WBH and 5.4 days with TNF + CBDCA + WBH (P less than 0.05). WBH, TNF, CDDP or CBDCA alone, TNF + CDDP, TNF + CBDCA, or TNF + WBH had no significant effect on tumor growth. In contrast, administration of TNF did not enhance the CDDP- or CBDCA-mediated dose limiting normal tissue toxicity. CDDP + WBH-mediated acute renal injury and CBDCA + WBH-mediated acute myelosuppression, as determined by blood urea nitrogen and peripheral blood cell counts, respectively, were not increased with the addition of TNF to either dual modality therapy. Histopathologically, addition of TNF produced no significant alterations in the kidney and the bone marrow as compared to CDDP + WBH or CBDCA + WBH. These data show that TNF enhanced the platinum + WBH-mediated antitumor effect without increasing normal tissue toxicity, suggesting that TNF may increase the therapeutic efficacy of CDDP or CBDCA combined with WBH.     

Cyclophosphamide-cisplatin versus cyclophosphamide-carboplatin in stage III-IV ovarian carcinoma: a comparison of equally myelosuppressive regimens

Between March 1985 and January 1987, 103 women with histologically proven stage III-IV ovarian carcinoma were randomly allocated to groups receiving monthly intravenous regimens of 1 g of cyclophosphamide/m2 plus either 60 mg of cisplatin (CDDP)/m2 or 150 mg of carboplatin (CBDCA)/m2 for 1 year unless disease progressed earlier. The groups were well balanced according to the stratification factors (age, histologic differentiation, extent of residual disease, and performance score), and both treatments were well tolerated and produced similar median first-course leukopenia (2,200 and 2,000 cells/microL) and thrombocytopenia (220,000 and 202,500 cells/microL). The CBDCA regimen was less emetogenic. After an interim analysis in January 1987 revealed superior progression-free survival for the group of 53 patients receiving CDDP (P = .005), the study was closed to further accrual. Those 24 patients still receiving CBDCA were encouraged to cross over to the CDDP-based regimen and 21 of them did. Following treatment crossover, the relative risk of death associated with original allocation to CBDCA receded from 1.79 to 0.97, indicating success of the salvage treatment using the CDDP-based regimen. This aborted study demonstrated the superiority of CDDP over CBDCA when the two platinum compounds were compared at equally myelosuppressive low doses in combination with 1 g of cyclophosphamide/m2. If CDDP is to be supplanted by CBDCA, larger, more myelosuppressive doses of CBDCA will be required. The platinum drug antitumor effect is a critically important therapeutic feature of this combination.     

A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240)

Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.     

环氧合酶-2抑制剂联合顺铂对卵巢癌抑制效果的研究

目的探讨选择性环氧合酶-2抑制剂与顺铂联合应用产生协同的抗卵巢癌作用。方法利用移植卵巢癌细胞株小鼠模型,研究环氧合酶-2抑制剂美洛昔康联合顺铂对小鼠生存期限、肿瘤生长以及小鼠体内前列腺素E2（prostaglandin E2,PGE：）水平、VEGF表达的影响。结果单独使用顺铂或美洛昔康均可延长DISS腹水小鼠的生存时间、抑制OVCAR-3肿瘤细胞的生长（P〈0．01）,并可降低恶性腹水小鼠的腹水及转移瘤小鼠血清中的PGE：水平（P〈0．01）,降低转移肿瘤组织中VEGF的表达（P〈0．01）。联合用药与单独使用顺铂或美洛昔康比较,明显增加对实验小鼠的抑制肿瘤效果。结论美洛昔康与顺铂联合使用对卵巢肿瘤的生长抑制有协同增效的作用。     

Synergism of cytotoxicity between cis-diaminedichloro-platinum-(ii) and cis-diamine(1,1-cyclobutanedicarboxylate)-platinum-(ii)

In an attempts to increase the antitumor effect and to reduce normal tissue toxicity, the combined cytotoxic effect of cis-Diamminedichloroplatinum (II) (CDDP) and cis-diammine(1,1-cyclobutane dicarboxylate) platinum (II) (CBDCA) was investigated using HeLa and colon 26 cell lines and the combination index (CI). Cytotoxicity of the combination of CDDP and CBDCA on 27 surgically resected specimens of human gastric and colorectal adenocarcinomas was also evaluated using the in vitro succinate dehydrogenase inhibition (SDI) test. The CI values varied with the dose ratio examined (1:1-1:6) of CDDP and CBDCA, with findings that CI<1, synergy, was obtained at fraction affected (Fa)>0.75 for HeLa cells and at Fa<0.9 for colon 26 cells in cases of a dose ratio of 1:1 to 1:2. Of all 27 clinical human adenocarcinomas, the succinate dehydrogenase (SD) activity was significantly lower in cancer cells concomitantly exposed to both CDDP and CBDCA than in those exposed to either drug alone. These positive effects of a combination of two platinum analogues on human malignant tissues have heretofore not been reported, which would warrant the clinical application of this combination for human malignant tumors.     

Antitumor activity against human tumor samples of cis-diamminedichloroplatinum(II) and analogues at equivalent in vitro myelotoxic concentrations

We compared the antitumor activity of cis-diamminedichloroplatinum(II) (cisplatin; CDDP) with three CDDP analogues: cis-diammine-1,1-cyclobutanedicarboxylateplatinum(II) (CBDCA), N-methyliminodiacetato-1,2-diamino(cyclohexane)platinum(II) (MIDP), and N-(2-hydroxyethyl)-iminodiacetato-1,2-diamino(cyclohexane)platinum (II) (HIDP). Fresh human tumor samples in the adhesive tumor culture system were utilized for this comparison. The equitoxic concentrations of all four drugs were derived based on their inhibitory activity against human bone marrow samples. For these normalized concentrations, CDDP proved to have a higher cytotoxic activity than its analogues. CBDCA's in vitro activity had a significant correlation with CDDP activity (r = 0.67) in vitro. However, the structurally similar substances MIDP and HIDP demonstrated a much greater degree of association (r = 0.90). Our data suggest that CBDCA, HIDP, and MIDP have overall less activity than CDDP when tested at equitoxic in vitro concentrations. Close association between CDDP and CBDCA also reflects known clinical experience with these two drugs, suggesting the method of comparison used here is probably appropriate. These conclusions, however, must be validated by clinical trials.     

Feasibility, activity, and change in the level of blood paclitaxel concentration after weekly paclitaxel therapy for a patient with recurrent ovarian cancer

The patient was a 59-year-old woman with recurrent ovarian cancer. A CT scan of the abdomen showed enlargement of abdominal para-aortic lymph nodes (PAN) after the primary operation and 8 cycles of the combination chemotherapy with paclitaxel (TXL) and carboplatinum (CBDCA). As a second line chemotherapy for the patient, weekly administration of TXL (60 mg/m2/week x 3 weeks) was given. The toxicity was acceptable and less pronounced than with the standard TXL + CBDCA therapy. Peak blood TXL concentration, about 90 ng/ml, was achieved 4 hours after the administration of TXL. The blood TXL concentration was below the detectable limit 48 h after the administration of TXL. An almost 50% shrinkage in the size of the PAN was obtained after 2 cycles of treatment. Good QOL is being maintained without any repeated aggravation of the tumor.     

Vitamin E succinate in combination with mda-7 results in enhanced human ovarian tumor cell killing through modulation of extrinsic and intrinsic apoptotic pathways

Adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to induce apoptosis in various human cancer cells while sparing normal cells. Vitamin E succinate (VES) is also known to exhibit antitumor activity against a number of human cancer cell lines. We hypothesized that a combination of the two agents would produce an enhanced antitumor effect in MDAH2774 human ovarian cancer cells. Treatment of MDAH2774 cells with Ad-mda7 plus VES resulted in enhanced antitumor activity that involved the activation of two apoptotic pathways. Activation of the extrinsic pathway was demonstrated by increased cell-surface Fas expression and cleavage of Bid and caspase-8. Activation of the intrinsic pathway was demonstrated by disruption of mitochondrial potential; and activation of downstream capase-9 and caspase-3 via cytochrome C release. In contrast, the combination of Ad-mda7 plus VES did not show any antitumor activity against normal fibroblasts, indicating selective tumor cell killing. Our in vitro results provide a basis for further preclinical testing of Ad-mda7 plus VES as a potential cancer treatment strategy.     

Cisplatin-incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

cis -Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)-poly(aspartic acid) (PEG-P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP-incorporated polymeric micelles (CDDP/m) were evaluated in comparison with those of CDDP. In vitro , CDDP/m exhibited 10-17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP/m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP/m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP/m treatment caused much less renal damage than CDDP. These results indicate that CDDP/m treatment can reduce CDDP-induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.     

Antitumor activity of a new platinum compound (glycolate-o,o') diammineplatinum (II) (254-S), against non-small cell lung carcinoma grown in a human tumor clonogenic assay system

(Glycolate-o,o') diammineplatinum (II) (254-S) is one of the platinum derivatives showing high activity against rodent solid tumors and lack of renal toxicity. We have used a human tumor clonogenic assay (HTCA) as a disease-oriented drug screening model for new antitumor drugs, in order to test the antitumor activity of 254-S against non-small cell lung carcinoma (NSCLC) and to compare its activity with that of cisplatin (CDDP) and of carboplatin (CBDCA). The overall in vitro response rate (defined as less than 50% survival of tumor colony forming units) for 254-S was observed in 10/29 and 20/30 evaluable specimens isolated freshly from NSCLC patients with continuous exposure at 1 and 10 micrograms/ml, respectively, indicating a positive dose-response relationship. Dose dependent cytotoxicity was also confirmed in 4 human tumor cell lines derived from NSCLC patients. The antitumor activity of 254-S was 3.6-fold that of CBDCA, but two-fifths that of CDDP. A comparison of these in vitro results with the toxic properties of 254-S such as low nephrotoxicity suggests that 254-S is a promising new drug against NSCLC.     

Combination chemotherapy of paclitaxel and cisplatin induces apoptosis with Bcl-2 phosphorylation in a cisplatin-resistant human epidermoid carcinoma cell line

PURPOSE: Paclitaxel (Taxol, TXL) is an antimicrotubule agent that stabilizes microtubules, arrests the cell cycle at the G(2)/M phase and induces apoptosis. In vitro drug sensitivity assays have shown that the combination of TXL and CDDP is more effective in CDDP-resistant ovarian carcinoma cell lines, with different cytotoxicities depending on the sequence of drug exposure. CDDP also shows poor results in human epidermoid carcinoma particularly of the head and neck region. METHODS: We investigated the effects and the molecular mechanisms of combination chemotherapy with TXL and CDDP in the CDDP-resistant cell line A431/CDDP2, and in its parental human epidermoid cell line A431/P. Drug sensitivity was determined using the MTS assay and cell cycle perturbation was analyzed using flow cytometry. DNA fragmentation was then analyzed and the protein levels of caspase-3 and Bcl-2, and phosphorylated of Bcl-2 were determined by Western blotting. RESULTS: In the drug sensitivity assay, exposure to CDDP prior to TXL was more effective than exposure TXL prior to CDDP in A431/P cells. In A431/CDDP2 cells, exposure to TXL prior to CDDP was more effective than exposure to CDDP prior to TXL. Exposure to TXL arrested the cells in the G(2)/M phase in both cell lines. In A431/CDDP2 cells, exposure to TXL prior to CDDP arrested the cells in the G(2)/M phase, an effect caused by either CDDP or TXL. Analysis of DNA fragmentation showed similar results to the drug sensitivity assay. Expression of caspase-3 protein active form was detected following exposure to TXL only and to the TXL/CDDP combination in both A431/P and A431/CDDP2 cells, but phosphorylation of Bcl-2 protein was detected only following exposure to TXL and only in A431/CDDP2 cells. CONCLUSIONS: These results indicate that exposure to TXL prior to CDDP plays a key role in circumventing CDDP resistance by phosphorylating Bcl-2 protein in the human epidermoid carcinoma cell line A431/CDDP2.     

Antitumor activity of a new platinum complex, (R)-(-)-2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II), against cisdiamminedichloroplatinum (II)-resistant murine leukemia cell line

Antitumor activity of a new platinum complex, (R)-(-)-2-aminomethylpyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) (DWA 2114 R) against cisdiamminedichloroplatinum (II) (CDDP)-resistant tumor was examined in in vitro and in vivo experiments. CDDP-resistant line was established from L 1210 mouse leukemia cells by continuous exposure to CDDP in dose-escalation manner. Six clones were isolated from parental resistant line and one of these clones, clone f, which was found to be highly resistant (30-40 fold) to CDDP, was used in the following experiments. Clone f showed 4-7 fold cross-resistance to DWA 2114 R and 11-19 fold to cisdiammine-1, 1-cyclobutanedicarboxylatoplatinum (II) (CBDCA) in in vitro growth inhibition assay. DWA 2114 R showed the most effective antitumor activity against mice transplanted with the resistant cells in the increase of life span (ILS%). About 100% of ILS and cured mice were observed in the treatment with DWA 2114 R. On the other hand, CDDP or CBDCA showed a little increase in the survival time (less than 40% of ILS) and all mice died. These results suggest that DWA 2114 R seemed to be more effective against CDDP-resistant tumors clinically than CDDP and CBDCA.