The efficacy of different antitumor therapies was evaluated in a study involving 53 patients with metastatic breast cancer resistant to anthracyclin antibiotics. Complete and partial regression of tumor was recorded following combined administration of vinorelbin and doxorubicin (27.3%) and taxanes (21.3%). Median therapeutic benefit duration was 22 and 28 weeks, respectively. Response frequency for mitomicin C + mitoxantron + methotrexate regimen was 11.1%. However, no objective therapeutic effects were observed in patients on ifosfamide + mitoxantron and regular 5-fluorouracil infusins.

A liposomal drug DaunoXome was used as a single agent for stage III-IV breast cancer in 9 patients. Response was recorded in 6; partial regression of tumor--3, and stabilization of disease--in 3 cases. Nausea and vomiting were among the most frequent side-effects; stage I leukopenia was observed in 4; stage II--3, stage III--2 patients. No cardiotoxicity was reported.

Sixty-six patients with multiple myeloma were divided into four groups: treatment with alpha-2a-interferon (reaferon) 3-5 mln MU/m2 alone (group); alpha-interferon + pulsed therapy with dexamethasone (group II); reaferon at high or low dose + different regemens of polychemotherapy (group III), and polychemotherapy followed by therapeutic support with melfalan and prednisone (MP) (control). Patients in group I untreated earlier with MP showed positive response in 80% while only 20% were in partial remission. Chemoresistance was broken in 86% (complete clinico-hematological remission--18%) following administration of high doses of alpha-interferon in conjunction with cytostatics. Reaferon + dexamethasone modality proved less effective. After chemoresistance was broken in 83%, tumor process reached a plateau. Low-dose reaferon was less effective, too, with complete remission never being reported. When administered in high doses as support therapy, it proved fairly effective, with median response being double that registered at low dosage or chemotherapy + MP. Whenever high-dose alpha-interferon tolerability is poor, dosage can be decreased; the patients may continue on low dosage or switch to MP support.

In isotonic medium, daunorubicin in the concentration range of 0.5-5.0 mg/ml of cells and doxorubicin in the concentration range of 0.2-1.0 mg/ml of cells caused hemoglobin (Hb) and K+ to efflux from red blood cells (RBC), to increase RBC size and to lower their deformability. Hb and K+ efflux rates were proportional to the antibiotic concentrations and remained stable for a few hours. Hb efflux did not change significantly in the 4-21 degrees C range (exempt at an experimental concentration of daunorubicin of 5.0 mg/ml of cells) but soared sharply at 37 degrees C. At the daunorubicin and doxorubicin concentration of 0.2 mg/ml of cells, Hb and K+ efflux virtually did not differ from control values. At the antibiotic concentration of 1.0 mg/ml of cells, 37 degrees C, Hb efflux rate was 0.34-5.6%, while that of K+(-) 1.0-8.2%, per hour, of possible maximum value. For the daunorubicin level of 5.0 mg/ml of cells, the respective values were 10 and 17%. At the daunorubicin concentration of 5.0 mg/ml, at 4 degrees C, Hb efflux from RBC was significantly higher than at 21 degrees C. RBC malleability, which was determined as their ability to pass through membrane filters having 3 mm dia pores, did not differ significantly from control values for a few hours antibiotic concentrations not exceeding 0.3 mg/ml of cells. At the antibiotic concentration of 1.0 mg/ml and higher RBC deformability dropped to zero within 10 min. ATP level in RBC practically remained identical to control values during incubation with the antibiotics for several hours.

Cytotoxicity genetic mechanisms such as induction of SOS-repair, excision repair and interstrand coupling induced by cycloplatam or ammine (cyclopentyl amine)-S(-) malatoplatinum (II), a new antitumor drug, were for the first time studied in comparison to those of the known drug cis-diammine dichloroplatinum (II) (DDP) in a model system of Escherichia coli. In the cells of E. coli the cycloplatam cytotoxicity was much lower than that of DDP. Both the drugs induced SOS-repair in E. coli PQ37. In a concentration of 25 microM DDP was 20 times as active as cycloplatam. In concentrations of 40 to 100 microM the difference leveled. Both the drugs induced interstrand coupling in specimens of pure DNA from calf thymus and E. coli. When the cells of the wild type E. coli AB1157 were incubated in the presence of the drugs only DDP induced the DNA interstrand coupling. No correlation between the DNA interstrand coupling induced by cycloplatam or DDP and cytotoxicity of the drugs was observed.

The article discusses the possible mechanisms of the antineoplastic effect of hypoxic bioreducing agents (HBA) when they are used in low nonhypoxic doses. Experimental and clinical studies provide evidence of the occurrence of stages which in administration of HBA into the organisms of the tumor-carrier may develop in succession, leading to stimulation of antineoplastic immunity: GBA activation in the hypoxic neoplastic tissue, conjugation of HBA metabolites with the macromolecules of the tumor cells, and presentation of the epitopes of neoantigens in association with the main complex of class I histocompatibility (MCH) cytolysis of these cells by T-killers. This process may be similar to that in contact sensitivity to low-molecular compounds (a variant of the reaction of delayed hypersensitivity [DH]) in the neoplastic focus. It is suggested that direct control of the effect of HBA on the immunocompetent and/or tumor cells may occur additively to or synergically with this process as the result of interaction of these compounds with the surface or intracellular receptors. It cannot be excluded that the activated HBA may force the endogenic ligands out of the nucleophilic centers of these receptors and realize receptor-mediated control of gene expression.

Changes were studied in the value for the nucleolar coefficient as were the percentage of large and compact nucleoli and numbers of Ag-NOR in the peripheral blood of patients with acute myeloblastic leukemia in order that resistant clones might be identified as early as possible. It has been ascertained that within 24 hours of the start of polychemotherapy "7 + 3" leukotic cells respond in different ways to the chemotherapeuticals employed depending on the outcome of the illness.

The expression of genes belonging to the Ada regulon of Escherichia coli under the action of mono- and bifunctional alkylating agents--high-efficiency antitumor HMM, ACNU, and BCNU preparations--was studied. The functional specificity of the alkA, alkB, and aidB1 genes concerning both the structure and volume of DNA alkylation and the specificity of cell preadaptation was revealed. Additional experimental evidence for the role of the aidB1 gene as a unique "hazard gene", a component of the E. coli ada operon, was obtained. A phenomenon of positive interference between alternative SOS and Ada responses was observed for the first time upon gene expression.

Chinese hamster fibroblasts CHL V-79 RJK were subjected to multistep selection in the presence of etoposide, known as an inhibitor of topoisomerase II and inductor of apoptosis. The karyotype of cells stably resistant to etoposide was analysed at progressive stages of selection using G-type staining of metaphase chromosomes. Multiple changes in the karyotype of resistant cells were observed at an early stage of selection (0.2 mg/ml of etoposide) and included: random chromosome breaks leading to formation of new chromosome markers, high frequency of aneuploid and polyploid cells, morphological instability and extracopy of q-shoulder of chromosome 1. On advanced stages of selection we observed an increased frequency of specific minute chromosome and the appearance of chromosomes with homogeneously or differentially stained regions (HSR and DSR). These data suggest that different mechanisms may be involved in developing cellular resistance to etoposide at progressive stages of selection.

The prospects of the endocytosis-mediated targeted delivery of antitumor drugs to the target cells by means of vector proteins, such as nerve growth factor (NGF), epidermal growth factor (EGF), and the oncofetal protein alpha-fetoprotein (AFP), are discussed. The high selectivity and efficiency of antitumor effects of synthetic covalent EGF- and AFP-conjugates with chemical agents (antitumor antibiotics) and antisense oligonucleotides are compared with individual biologically active compounds in in vitro and in vivo animal studies. The molecular mechanisms of action of the above conjugates have been studied. Evidence is given for the fact that it is expedient to use them to overcome multidrug resistance in the clinical setting. The findings are the first important step in designing novel target antitumor drugs based on biologically active vector proteins showing their effects by receptor-mediated endocytosis.

Doxorubicin was acylated with estrone 3-hemisuccinate. The modified derivative exhibited high antiproliferative activity in vitro toward cell cultures of the MCF-7 human mammary adenocarcinoma and HepG2 human hepatoma.