didimethylsulfoxide-dichloroplatinum(ii) and Breast-Neoplasms

Twenty-four patients with refractory Stage IV breast cancer were treated with platinol (100 mg/m2 i.v. Day 1) and 5-fluorouracil (1000 mg/m2 as a continuous infusion over 24 h daily for 5 days). Objective responses occurred in 12 of 24 patients (50%). The median duration of response was 4.9 months. Platinol and 5-fluorouracil in combination are active agents in patients with refractory breast cancer, and clinical trials are warranted in previously untreated patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Male; Middle Aged; Organoplatinum Compounds; Remission Induction

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Carmustine; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Mastectomy, Segmental; Organoplatinum Compounds; Tamoxifen

We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agen

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carboplatin; Carmustine; Drug Resistance; Drug Screening Assays, Antitumor; Drug Synergism; Fibrosarcoma; Humans; Indazoles; Mammary Neoplasms, Animal; Mice; Organoplatinum Compounds; Tumor Cells, Cultured; Tumor Stem Cell Assay

Neoadjuvant chemotherapy can be used before radiotherapy to combat microscopic metastatic loci and to facilitate irradiation. Improvement in the survival time by impeding the dissemination of metastases seems to be real for breast cancer, but has not been observed to date in randomized studies of ENT cancers. Neoadjuvant chemotherapy in Hodgkin's disease has improved survival time and tolerance to irradiation, allowing a lowering of the total doses used and the volumes irradiated. In breast and ENT cancers, it has become possible, due to tumor regression, to replace mutilating treatments with more conservative ones consisting of radiotherapy alone, without increasing the risk of local relapse. Indeed, it is in this domain that neoadjuvant chemotherapy is the most useful. Two important conditions must be met for its successful application: a) a sufficiently effective regimen must be chosen, in order to prevent tumor growth prior to irradiation (which would aggravate the prognosis); and b) an accurate identification and localization of the tumor before undertaking any treatment so as to not detract from the effectiveness of the radiotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Hodgkin Disease; Humans; Male; Mechlorethamine; Methotrexate; Neoplasm Metastasis; Organoplatinum Compounds; Otorhinolaryngologic Neoplasms; Prednisone; Procarbazine; Random Allocation; Thiotepa; Vinblastine; Vincristine

Our previous method of adoptive immunotherapy using IL2-cultured autologous lymphocytes consists of (1) in vitro sensitization by sonicated autologous tumor extract, (2) the induction and proliferation of active CTL by crude IL2, and (3) the preadministration of OK-432 for the augmentation of the therapeutic effect. Here we describe a new method to augment the therapeutic effect of OK432-combined AIT. In BALB/c mice with advanced malignant ascites (MOPC 104E), serial therapy with OK-432, cyclophosphamide and AIT significantly prolonged the survival compared with other therapeutic schedules through synergism between host's effector cells induced by immuno-chemotherapy and transferred killer cells. Many patients with advanced malignancies, for example, unresectable gastrointestinal cancer, locally advanced breast cancer or lung metastases of breast cancer, respond to such immuno-chemo-lymphocytotherapy, while previous OK432-combined AIT was effective only in malignant pleural effusion or metastatic liver tumor from breast cancer or peritoneal dissemination of gastric cancer.

Topics: Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Immunization, Passive; Interleukin-2; Killer Cells, Natural; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neoplasms, Experimental; Organoplatinum Compounds; Picibanil; Transplantation, Autologous

Adding Fluosol-DA and carbogen breathing to treatment with various anticancer drugs can result in a significant enhancement of tumor growth delay compared to the drug and air breathing. The optimal conditions for tumor response depend upon the drug, oxygenation level and duration, and perfluorochemical emulsion dosage. In this study, representative chemotherapeutic agents from several classes were tested in a tumor growth delay assay in combination with various doses of Fluosol-DA under conditions of normal aeration, carbogen breathing either for 1-2 hours or 6 hours, or with hyperbaric 100% oxygen (3 atmospheres) breathing for 1 hour to determine whether the antitumor activity of these drugs would be improved.

Topics: Animals; Antineoplastic Agents; Bleomycin; Breast Neoplasms; Carbon Dioxide; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Drug Combinations; Fibrosarcoma; Fluorocarbons; Fluorouracil; Humans; Hydroxyethyl Starch Derivatives; Male; Melphalan; Methotrexate; Mice; Mice, Inbred C3H; Mice, Nude; Neoplasm Transplantation; Neoplasms; Organoplatinum Compounds; Oxygen; Tumor Cells, Cultured