Naoya Horichi

Pharmacokinetics of (glycolato-0,0′)-diammine platinum (II), a new platinum derivative, in comparison with cisplatin and carboplatin

SummaryThe pharmacokinetics of (glycolato-0,0′)-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 μg/ml and 959 μg/min per ml for 254-S, 3.09 μg/ml and 208 μg/min per ml for cisplatin, and 19.90 μg/ml and 3446 μg/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.

Phase II study of irinotecan and carboplatin in patients with the refractory or relapsed small cell lung cancer

We examined the safety and efficacy of the combination of irinotecan plus carboplatin in patients with refractory or relapsed small cell lung cancer (SCLC). Patients with previously treated SCLC were eligible. Patients were treated every 3 weeks with carboplatin (with a target area under the concentration versus time curve of 5 mg min/ml using the Calvert formula on day 1) plus irinotecan (50 mg/m(2) on days 1 and 8). From May 2000 to January 2002, 24 patients were eligible. None of the 22 patients achieved a complete response, but 15 achieved a partial response with an overall response rate of 68.2% (95% confidence interval, 45.1-86.1%). In 13 patients with sensitive disease, the response rate was 92.3% (95% confidence interval, 64.0-99.8%). The median survival time (MST) was 194 days (range 27-605 days). The MST did not differ significantly between patients with sensitive disease (245 days) and those with refractory disease (194 days, P=0.88). One patient died of treatment-related sepsis. Grade 3-4 hematologic toxicities included leukopenia in 58% of patients, neutropenia in 63%, thrombocytopenia in 58%, and anemia in 67%. Grade 3 diarrhea developed in 21% of patients and grade 3-4 infection in 13%. No patients had grade 4 diarrhea or grade 3-4 nausea and vomiting. This regimen is effective and well tolerated in patients with relapsed or refractory SCLC. However, the search for even more active regimens should be continued.

Enhancement of sensitivity to tumor necrosis factor α in non-small cell lung cancer cells with acquired resistance to gefitinib

Tumor cells that have acquired resistance to gefitinib through continuous drug administration may complicate future treatment. To investigate the mechanisms of acquired resistance, we established PC-9/ZD2001, a non-small-cell lung cancer cell line resistant to gefitinib, by continuous exposure of the parental cell line PC-9 to gefitinib. After 6 months of culture in gefitinib-free conditions, PC-9/ZD2001 cells reacquired sensitivity to gefitinib and were established as a revertant cell line, PC-9/ZD2001R. PC-9/ZD2001 cells showed collateral sensitivity to several anticancer drugs (vinorelbine, paclitaxel, camptothecin, and 5-fluorouracil) and to tumor necrosis factor α (TNF-α). Compared with PC-9 cells, PC-9/ZD2001 cells were 67-fold more sensitive to TNF-α and PC-9/ZD2001R cells were 1.3-fold more sensitive. Therefore, collateral sensitivity to TNF-α was correlated with gefitinib resistance. PC-9/ZD2001 cells expressed a lower level of epidermal growth factor receptor (EGFR) than did PC-9 cells; this down-regulation was partially reversed in PC-9/ZD2001R cells. TNF-α-induced autophosphorylation of EGFR (cross-talk signaling) was detected in all three cell lines. However, TNF-α-induced Akt phosphorylation and IκB degradation were observed much less often in PC-9/ZD2001 cells than in PC-9 cells or PC-9/ZD2001R cells. Expression of the inhibitor of apoptosis proteins c-IAP1 and c-IAP2 was induced by TNF-α in PC-9 and PC-9/ZD2001R cells but not in PC-9/ZD2001 cells. This weak effect of EGFR on Akt pathway might contribute to the TNF-α sensitivity of PC-9/ZD2001 cells. These results suggest that therapy with TNF-α would be effective in some cases of non-small-cell lung cancer that have acquired resistance to gefitinib.

Tumor dimension and prognosis in surgically treated lung cancer: for intentional limited resection.

Tumors with a maximum dimension of 3 cm are categorized as T1, whereas those greater than 3 cm are T2 by TNM classification. Some physicians suggest that early-stage peripheral lung cancer should have a maximum tumor diameter of 2 cm and that limited surgery (segmentectomy without lymph node dissection) is acceptable for the patients. In this study, the relationship between the tumor dimension and prognosis was analyzed in 207 patients with surgically treated primary non–small-cell lung cancer (SCLC). The 5-year survival rate of those with tumors 3 cm or less and without lymph node (LN) metastases was 86%, which was significantly higher than that of those with tumors more than 3 cm and without hilar and mediastinal LN metastases (65%) (p < 0.05). However, 33% of the patients with tumors 3 cm or less had LN metastases, and the 5-year survival rate did not differ between those with tumors 3 cm or less (60%) and those with tumors more than 3 cm (54%). Twenty-eight percent of patients with tumors 2 cm or less had LN metastases, and the 5-year survival rate of the patients with tumors 2 cm or less was 62%. The 5-year survival rate of those with tumors 2 cm or less and without LN metastases was 88%. Forty-six patients with tumors 2 cm or less included 5 cases with an intrapulmonary metastasis in the same lobe (11%). In conclusion, a size of 3 cm is an appropriate boundary as the T factor. Because those with tumors 2 cm or less have a relatively high percentage of LN metastases, intraoperative frozen sections of LN should be considered for those undergoing limited surgery for primary non-SCLCs 2 cm or less. Intrapulmonary metastases also should be considered for those undergoing limited surgery even if the maximum dimension of the primary tumor is less than 2 cm.

Outcome Following Surgery for Primary Lung Cancer with Interlobar Pleural Invasion

PurposeTo determine whether interlobar pleural invasion into the adjacent lobe (interlobar P3) should be assessed as T3 according to the tumor-node metastasis classification.MethodsSurgically treated patients with primary lung cancer (n = 322) were analyzed.ResultsTumors with interlobar P3 had a significantly lower incidence of mass screening detection, a higher occurrence rate of squamous cell carcinoma, and a larger tumor diameter than tumors without interlobar P3. The lymph node metastatic rate did not differ between the patients with and without interlobar P3. The 5-year survival rate of patients with interlobar P3 was 63% and the rates of other patients were 56% with T1 disease, 57% with T2, 31% with T3, and 19% with T4. The survival rate for patients with interlobar P3 was higher than for those with T3 without interlobar P3 (P < 0.05). The 5-year survival rate of the patients with interlobar P3 was lower in adenocarcinoma (39%) than in squamous cell carcinoma (69%, P < 0.01). The results were similar when the analysis was restricted to patients without lymph node metastasis. In adenocarcinoma, the survival rate for interlobar P3 was between the rates for T2 (53%) and T3 (13%) without interlobar P3, whereas in squamous cell carcinoma, the survival rate for interlobar P3 was between the rates for T1 (88%) and T2 (54%) without interlobar P3.ConclusionTumors with interlobar P3 should be classified as T2 only in squamous cell carcinoma.

Phase I study of the combination of gemcitabine and nedaplatin for treatment of previously untreated advanced non-small cell lung cancer

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0-2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m(2)), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47-75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4-59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m(2) of gemcitabine and 100 mg/m(2) of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.

Drug Accumulation and Efflux Do not Contribute to Acquired Gefitinib Resistance

Gefitinib is one of tyrosine kinase inhibitors and often has dramatic effect on non-small-cell lung cancer (NSCLC) expressed mutant EGFR. However, most of the patients who respond to gefitinib eventually experience tumor recurrence. To clarify the mechanism of this acquired resistance, we examined cellular accumulation and efflux of gefitinib using gefitinib sensitive and resistant NSCLC cells. We used four NSCLC cell lines; PC-9: hypersensitive to gefitinib, expressed a 15 bp deletion mutant EGFR, PC-9/ZD2001 and PC-9/ZD1kl: acquired-resistant to gefitinib, PC-9/ZD2001R: a revertant reacquired sensitivity to gefitinib. To measure the cellular accumulation, cells were exposed to 1 µM of [14C]gefitinib for 3 to 30 min at 37 °C For the measuring of drug efflux, cells were exposed gefitinib for 30 min, and then cells were washed and further incubated in drug free medium. After the incubation, cells were lysed and the radioactivities were counted. There was no significant difference of gefitinib accumulation in those cell lines (range 642–731 µmol/g protein at 30 min). The efficiencies of gefitinib-efflux were almost the same in those cell lines (about 80% of gefitinb was discharged at 15 min). According these findings, we demonstrated that acquired resistance to gefitinib did not depend on cellular accumulation or efflux of this drug.

Epidermal Growth Factor (EGF) Receptor Kinase Activity is Required for Tumor Necrosis Factor (TNF)-α Mediated Intestinal Epithelial Survival

Epidermal growth factor receptor (EGFR) plays a key role in the regulation of normal cellular process and in the hyper-proliferative diseases such as cancer. Recently it has been demonstrated that TNF-induced apoptosis is augmented by inhibition of EGFR. In the present study we demonstrated that EGFR expression and its tyrosine kinase activity is required for TNF-induced cell survival using EGFR tyrosine kinas inhibitor, AG1478 in stable transfected colon intestinal epithelial EGFR-/- cells model transfected with either wild-type (wt), or kianse inactive (ki) EGFR. Furthermore, for the first time, we demonstrated that EGFR transactivation leads to other ErbB receptors through TNF induced transactivation of ErbB family receptors (EGFR, ErbB2 and ErbB4). Mutational analysis demonstrated that EGFR autophosphorylation sites of Y1068 and Y1086, a subsequent PI 3-kinase/Akt activation sites, is required for TNF mediated transactivation of EGFR, ErbB2 and 4 through Src kinase activity and cell survival. Like as Src kinase inhibitor, PI 3-kinase inhibitor enhanced TNF-induced apoptosis, but not MAP kinase inhibitor. From the present study we postulate that EGFR and EGFR tyrosine kinase involving Y1068 and Y1086 is critical in inducing TNF-initiated colon epithelial cell apoptosis through activation of the PI 3-kinase/AKT pathway. This novel observation has significant implications for understanding the role of EGFR regulation in maintaining intestinal epithelial cell homeostasis in an environment of chronic inflammation, injury and repair, such as inflammatory bowel disease and tumorigenesis.