Cis-diaminedichloroplatinum Research Articles

Effects of asymmetry and bulky substituents in amine ligands of cis-Di(amine)dichloroplatinum complexes on the structure of adducts formed with adjacent guanines in nucleic acids

Platinum adducts obtained from the reaction of 3′-O,5′-O-phosphodiguanosine, r(GpG), with the asymmetric complexes cis-[PtCl2L(L′)](L = NH3; L′= alkylamine such as NH2Me, NH2Et, NHMe2and NHEt2; LL′=N,N-dimethylethylenediamine) have been structurally characterized by 1H NMR techniques. Two different adducts, in which platinum co-ordinates to the N7 sites of both guanines, were obtained as geometrical isomers, one with the NH3group cis to the 5′ base and the other with the alkylamine cis to it. Apparently, the structures of these platinum adducts, cis-[PtL(L′)(GpG-N7,N7)]+, are similar to that of the known cis-[Pt(NH3)2(GpG-N7,N7)]+, i.e. with an anti-anti configuration and with the N conformer of the sugar as the 5′ residue. However, the asymmetric character of the non-leaving group induces a slight but significant deviation in the relative orientation of the two guanines which increases with increasing bulkiness of the alkylamine group.

Adjunctive treatment for recurrent childhood ependymoma of the IV ventricle: chemotherapy with CDDP and MCNU

The prognosis of recurrent IV-ventricle ependymoma in children is poor. Three cases of recurrent ependymoma were treated with combination chemotherapy using cis-diamine dichloro platinum (II) (CDDP) and methyl-6-(3-(2-chloroethyl)-3-nitrosoureido)-6-deoxy-alpha-D-glucopyrano side (MCNU). The patients were 2-, 3-, and 6-year-old boys. The interval between the first operation with irradiation and recurrence was 1 year and 5 months to 2 years. Two cases showed a recurrence at the original site; in the other case, a right sylvian tumor deposit was found via computed tomography. The therapeutic regiment for recurrent ependymomas was as follows: (1) the tumor was debulked if possible; (2) additional local irradiation of 30 Gy was administered; (3) combined treatment of 100 mg/m2 CDDP and 80 mg/m2 MCNU over 24 h was given 5 times with an interval of 6 weeks between treatments. The patients tolerated the therapy well with only mild side effects. Remission lasted 1 year in two patients and has lasted for 8 months in one.

Preoperative hyperthermia combined with radiotherapy and chemotherapy for patients with incompletely resected carcinoma of the esophagus.

Two hundred eighty-nine patients with squamous cell carcinoma of the esophagus underwent subtotal esophagectomy from December 1965 to June 1986. Resection of esophageal carcinoma was absolutely noncurative in 64 patients (20%) due to invasion to the surrounding structures. These 64 patients were subdivided as follows into three groups based on the type of preoperative treatment: Group I included 16 patients without preoperative treatment; Group II included 38 patients with preoperative radiotherapy combined with chemotherapy (average doses: radiation 37.3 Gy, 1-(2-tetrahydrofuryl)-5-fluorouracil [tegafur] 8.4 g); Group III included 10 patients who underwent preoperative hyperthermia (42 degrees C to 45 degrees C) combined with chemotherapy and radiotherapy (average doses: radiation 33 Gy, bleomycin 33.9 mg, or cis-diamine dichloroplatinum 75 mg, hyperthermia 6.2 times). There were no significant differences in terms of postoperative therapy among the three groups. The median survival times for patients in Groups I, II, and III were 6, 7.5 and 11 months, respectively. The 2-year survival rates for patients in Groups I, II, and III were 0, 15.6%, and 34.3%, respectively. The prognosis in Group III was superior to that for Group I (P less than 0.05) and Group II. These results suggest that preoperative hyperthermia combined with radiotherapy and chemotherapy could prolong survival even in patients who have had noncurative resection.

A Case of Pancreatic Cancer With Liver Metastasis Which Responded to Chemotherapy

A case of pancreatic cancer with liver metastasis is reported, in which chemotherapy had a marked effect, with the responses clearly documented. The patient was a 59-year-old male who experienced epigastric pain in February 1985, upper gastrointestinal X-ray examination revealing extragastric compression by the pancreas. He visited the National Cancer Center Hospital, Tokyo, in April 1985 and the diagnosis of pancreatic cancer with liver metastasis was made using the imaging procedures of ultrasonography, computed tomograph scanning and endoscopic retrograde cholangiopancreatography as well as by biochemical and serological tests. At the time a 5 cm tumor was palpable in the middle upper abdomen. The patient was treated with Cis-diaminedichloro platinum, tegafur, and 5-fluorouracil, successively, and the abdominal tumor gradually diminished, finally becoming impalpable. The response was evaluated as one of partial responses (PR) by ultrasonography, and the improvement substantiated by computed tomography and tumor markers.

Immunostimulatory effect of Cis-diamine dichloroplatinum (II)

Cis-diamine dichloroplatinum (II) (DDP) injected i.p. or i.v. at the dosage of 0.83 mg/kg to BALB/c mice on days 0, 7 and 14 elicited antibodies against proteins (RSA, BGG) and haptens (TNP, FITC) detectable by ELISA or by passive haemagglutination. Significant increase in antibody production was observed with either route of DDP application. A similar set of antibodies against antigens which do not cross-react with the immunizing proteins was observed when mice were immunized with complexes formed by an in vitro incubation of RSA and BGG with DDP. Thus, proteins modified in vivo or in vitro by DDP may stimulate the production of antibodies of unexpected specificities.

Current status of transcatheter management of neoplasms.

Transcatheter arterial infusion and arterial embolization are employed in the treatment of various neoplasms. In patients with carcinoma of the colon metastatic to the liver, the hepatic arterial infusion (HAI) of floxuridine and Mitomycin produced a 55% partial response and a 12% complete response, as well as an improved median survival of 18 months. In metastatic breast carcinoma, a 30% response was achieved. In some cases, proximal embolization of aberrant hepatic arteries was performed to redistribute the hepatic flow to a single vessel to assist infusion of the entire liver using a single catheter. Devascularization by hepatic artery embolization has also been used to treat hepatic neoplasms. Arterial occlusion of renal carcinoma, followed after four to seven days by nephrectomy and hormonal therapy, produced a 36% response rate in 49 patients with distant metastases. In 14 patients with osteosarcoma treated with cis-diaminedichloroplatinum (CDDP) arterial infusion, a 57% response rate was achieved. Benign bone tumors were treated with arterial occlusion with a 60% response rate. Tumors of the pelvis were managed by bilateral internal iliac artery infusion using CDDP. In 21 patients with recurrent bladder carcinoma, control of pain and hematuria and prolonged survival were achieved.

Nutrients, vitamins and minerals as therapy

Nutrients as therapy for patients with cancer are important as adjunctive therapy, i.e., adequate nutrition may be important for the success of whatever form of therapy is administered. Diets deficient in certain amino acids have some selectivity when tested against experimental tumors propagated in vivo. Such diets have had limited clinical trial and have been characterized by poor patient acceptance. Enzymes that produce deficiencies of certain amino acids, e.g., asparaginase, glutaminase, methioninase appear to offer a more reasonable approach to development of selective amino acid deficiencies in man. Trace metals in excessive amounts may be toxic or carcinogenic to the host. Two heavy metal salts, Cis-diamine dichloroplatinum and gallium nitrate, have recently been shown to have anti-neoplastic effects in man. There is no conclusive evidence that vitamins, administered in large doses, have significant antineoplastic effects although large doses of vitamin A, vitamin C, and vitamin B12 have been used for this purpose. In contrast, certain vitamin analogs such as folate antimetabolites can cause tumor regression and are useful clinical treatment. An enzyme, carboxypeptidase G1, by splitting naturally occurring folates, may also have promise as a method of producing enzymic folate deficiency.

Cis-platinum chemotherapy in head and neck cancers.

Sixteen patients with advanced head and neck carcinomas were treated with cis-diaminedichloro platinum chemotherapy; seven preoperatively and nine for recurrent disease. Cis-platinum was given by 24-hour infusions of 80 mg/m2 every three weeks. There was 50% regression in 38% (6) of the patients; another 38% (6) had 25% to 50% regression. Toxicity was minimal, with vomiting occurring in 75% (12) of the courses, renal toxicity in 6% (2), leukopenia in 13% (4), thrombocytopenia in 9% (3), and anemia in 31% (10). Of the seven patients who had serial audiograms, only one experienced ototoxicity. Cis-platinum, given by 24-hour infusion, was effective in reducing tumor bulk in 75% (12) of the patients, with advanced head and neck carcinomas, without undue morbidity.