didimethylsulfoxide-dichloroplatinum(ii) and Lung-Neoplasms

Survival in patients with locally advanced (stage III Mo) and metastatic (Ml) non-small-cell lung cancer (NSCLC) is short. Phase II studies have reported objective responses ranging from 20% to 60% using cisplatin-based chemotherapeutic regimens, yet few have shown improvement in median survival. In our phase II pilot studies with cisplatin (CDDP) and etoposide (VP-16), we observed a 26% response rate; with CDDP, VP-16, and mitomycin-C, a 38% response rate was obtained in advanced NSCLC patients. A total of 156 consecutive patients with locally advanced and metastatic NSCLC were randomized to one of three treatment arms to determine whether the chemotherapy protocols had any effect on response rate and median survival in a large, randomized study. Arm 1 consisted of CDDP (120 mg/m2 x 3 weeks); arm 2, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 given i.v. on days 1-3), repeated every 3 weeks; and arm 3, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 on days 1-3) given every 3 weeks, plus mitomycin C (10 mg/m2 on days 1, 21, and 42, then every 6 weeks, for a maximal dose of 100 mg). After 71 patients had been enrolled in the study, we stopped accrual in the CDDP arm due to a lack of response [1 complete response (CR) in 24 patients; 4%] and continued enrollment in the two combination-chemotherapy arms. In the CDDP/VP-16 arm a 30% response rate [1 CR, 18 partial responses (PRs)] was obtained, and in the CDDP/VP-16 mitomycin C arm a 26% response rate (4 CRs, 11 PRs) was seen among a total of 150 evaluable patients. Responses were observed in 31% of patients with favorable performance status (PS) (ECOG 0-1) vs 14% in patients with a poor PS (ECOG 2-3). Of patients with locally advanced disease (III Mo), 17 (33%) obtained an objective response, compared with 20 patients (20%) with metastatic disease. Median survival was 18 weeks in the CDDP arm, 35 weeks in the CDDP/VP-16 arm, and 37 weeks in the CDDP/VP-16/mitomycin C arm. The median survival in the multimodal chemotherapy arms was significantly greater than that obtained with CDDP alone. Toxicity was predominantly myelosuppression in the mitomycin C-containing arm (27%, wtto grade 3-4). Our study shows that combination chemotherapy using CDDP/VP-16 is active and safe in the treatment of advanced NSCLC patients with a good performance status. The addition of mitomycin C did not improve the therapeutic response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Organoplatinum Compounds; Prognosis; Prospective Studies; Remission Induction; Survival Analysis

cis-Diamminedichloroplatinum(II) (CDDP) induced G2-phase arrest in PC-9 human cancer cells. To elucidate how CDDP acts on cell-cycle regulation, we analyzed the effect of CDDP on cell-cycle regulators such as p34cdc2 protein kinase. p34cdc2 protein kinase activity was maximum in G2 phase and decreased after G2/M transition in synchronized PC-9 human lung cancer cells. Evidence for a phosphorylated p34cdc2 protein kinase complexed with cyclin B was obtained from cells in G2 phase and the p34cdc2 protein kinase appeared to be dephosphorylated at M phase. After exposure to CDDP in G1 phase, PC-9 cells were arrested in G2 phase. The activation of p34cdc2 protein kinase was inhibited by CDDP. Cyclin A and wee-I kinase were not affected by the exposure to CDDP. Cyclin B was degraded in M phase in PC-9 cells. Exposure to CDDP did not affect the degradation of cyclin B. Our data suggest that the effect of CDDP on cell-cycle phase might be regulated by the dephosphorylation of p34cdc2 protein kinase. To determine whether the p34cdc2 protein kinase is a primary target for CDDP, we examined the direct effect of CDDP on tyrosine dephosphorylation of p34cdc2 protein kinase in cellular extracts. Cell lysates from synchronized PC-9 in G2 phase were immunoprecipitated with p13-Sepharose beads. In vitro dephosphorylation of phosphotyrosine of p34cdc2 protein kinase was observed after exposure to okadaic acid in a concentration-dependent manner. The dephosphorylation of p34cdc2 protein kinase by okadaic acid was inhibited by CDDP. We hypothesize that inhibition of p34cdc2 dephorphorylation by CDDP is important for its growth-inhibiting properties.

Topics: CDC2 Protein Kinase; Cell Cycle Proteins; Cyclins; G2 Phase; Humans; Immunoblotting; Lung Neoplasms; Mitosis; Nuclear Proteins; Organoplatinum Compounds; Phosphorylation; Protein Kinases; Protein-Tyrosine Kinases; Tumor Cells, Cultured

The distribution of cis-diamminedichloroplatinum (CDDP) was studied in 23 patients undergoing surgical resection of brain tumors metastatic from lung cancer. CDDP (100 mg/m2) was administered intravenously (i.v.) or intra-arterially (IA) at the time of surgery, and various fluids and tissues were sampled for measurement of drug concentration. Comparison of the two routes of administration disclosed that the plasma level was slightly lower after IA than after i.v. infusion, whereas there was no difference between the two routes in terms of drug diffusion into the brain tissue adjacent to the tumor. However, IA administration resulted in an intratumoral drug concentration twice as high as that achieved with i.v. infusion. The tumor:plasma and tumor:adjacent brain ratios of drug concentration after IA injection were also twice those measured after i.v. administration. The distribution pattern of CDDP is characteristic of water-soluble agents. All patients experienced tolerable nausea and vomiting. Creatinine clearance was moderately reduced in ten cases, but no serious renal toxicity was observed. Seizures occurred postoperatively in nine patients. Infrequent side effects were myelosuppression, ototoxicity, and postoperative intracranial bleeding. All adverse effects disappeared with conservative treatment or no intervention.

Topics: Aged; Body Fluids; Brain Neoplasms; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Tissue Distribution

Parenchymal brain tumors, which were metastases of primary lung cancer, were surgically removed from 25 patients. During the operation, patients were administered (intravenous or intracarotid) 100 mg/sq m of cis-diamminedichloroplatinum (CDDP) and postoperatively, they received intravenous CDDP at 3-month intervals for 1 year. The results of this mode of treatment were compared with those obtained in 25 patients who underwent the same surgery but received other anticancer agents and in 39 patients who received no postoperative chemotherapy. Patients in the CDDP-treated group survived much longer than both of the other treatment groups. In the CDDP, but not in the other two groups, survival was significantly longer in patients who had undergone resection of their lung tumors than in those who had not. The stage of lung cancer was not found to significantly influence survival time among CDDP-treated patients. Brain metastasis was the cause of death in 12% of the patients who received CDDP, in 16% those treated with other drugs, and in 26% of those who received no chemotherapy. The incidence of local and remote intracranial tumor recurrence, including meningeal carcinomatosis, was similar in the three groups. However, the mean interval from resection of the metastatic brain tumor to local or remote recurrence was longer in the CDDP-treated group than in the other two groups, and the 2-year-survival rate was significantly higher after CDDP administration. These results suggest that CDDP may be useful in the therapy of metastatic brain tumors derived from lung cancer.

Topics: Brain Neoplasms; Carcinoma; Combined Modality Therapy; Humans; Lung Neoplasms; Meningeal Neoplasms; Neoplasm Recurrence, Local; Organoplatinum Compounds; Preoperative Care; Retrospective Studies; Survival Rate

Serial serum erythropoietin (EPO) levels were measured in 12 adult lung cancer patients during cancer chemotherapy. In major cases, EPO levels increased significantly after chemotherapy while the hemoglobin (Hb) remained at initial levels. EPO fell gradually or rapidly to initial levels after a peak, although the patients were anemic. The increase of EPO levels was linearly related to the decrease in Hb (y = 17.48x + 1.003). The mechanism of the rapid increase of EPO is not simply explained by anemia, but might be related to new synthesis, corresponding to depressed bone marrow.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds

We treated a patient with lung cancer in whom a hypercoagulopathy was induced acutely by chemotherapy. He received systemic chemotherapy twice and in both instances developed disseminated intravascular coagulopathy (DIC), accompanied by acute decrements of the peripheral platelet count and plasma fibrinogen, an increment of the fibrin degradation products (FDP), and bleeding tendency with the appearance of skin purpura. In each instance, the plasma thrombosis-inducing activity (TIA) appeared one to three days after chemotherapy and subsided subsequently.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Disseminated Intravascular Coagulation; Fibrinogen; Humans; Lung Neoplasms; Male; Organoplatinum Compounds; Platelet Count; Tegafur; Thrombosis; Vindesine

The renal function in 26 patients with malignant tumors (19 non-small cell lung cancers, 4 small cell lung cancers, 1 malignant lymphoma, 1 esophageal cancer, 1 malignant thymoma) who were treated with 43 times combination chemotherapy including CDDP was evaluated prospectively, by measuring of creatinine clearance (Ccr), fractional excretion of beta-2-microglobulin (FE beta 2MG), urinary N-acetyl-beta-glucosaminidase (NAG), and 131I-OIH or 123I-OIH renogram. The comparison of renogram and other parameters showed significant change in renogram (23/43, 53.5%), however other parameters such as Ccr, FE beta 2MG, NAG altered in only 10.3-34.9%. After the administration of CDDP, renograms were divided into distinctive 4 patterns as follows: 1) aggravation of obstructive pattern 2) early plateau pattern in excretory phase 3) intermittent pattern in excretory phase 4) prolongation of secretory phase. We consider these patterns suggest some obstructive change of urinary tract microscopically, that is proximal tubules damage due to cellular necrosis and tubular dilatation by CDDP. 131I-OIH or 123I-OIH renogram in delayed phase is useful for detection of renal dysfunction by CDDP administration.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Iodohippuric Acid; Kidney; Kidney Diseases; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Radioisotope Renography