Selected drugs with reported secondary cell-differentiating capacity prime latent HIV-1 infection for reactivation.

Reactivation of latent HIV-1 infection is considered our best therapeutic means to eliminate the latent HIV-1 reservoir. Past therapeutic attempts to systemically trigger HIV-1 reactivation using single drugs were unsuccessful. We thus sought to identify drug combinations consisting of one component that would lower the HIV-1 reactivation threshold and a synergistic activator. With aclacinomycin and dactinomycin, we initially identified two FDA-approved drugs that primed latent HIV-1 infection in T cell lines and in primary T cells for reactivation and facilitated complete reactivation at the population level. This effect was correlated not with the reported primary drug effects but with the cell-differentiating capacity of the drugs. We thus tested other cell-differentiating drugs/compounds such as cytarabine and aphidicolin and found that they also primed latent HIV-1 infection for reactivation. This finding extends the therapeutic promise of N'-N'-hexamethylene-bisacetamide (HMBA), another cell-differentiating agent that has been reported to trigger HIV-1 reactivation, into the group of FDA-approved drugs. To this end, it is also noteworthy that suberoylanilide hydroxamic acid (SAHA), a polar compound that was initially developed as a second-generation cell-differentiating agent using HMBA as a structural template and which is now marketed as the histone deacetylase (HDAC) inhibitor vorinostat, also has been reported to trigger HIV-1 reactivation. Our findings suggest that drugs with primary or secondary cell-differentiating capacity should be revisited as HIV-1-reactivating agents as some could potentially be repositioned as candidate drugs to be included in an induction therapy to trigger HIV-1 reactivation.

Evidence of the role of protein kinase C during aclacinomycin induction of erythroid differentiation in K562 cells.

At subtoxic concentrations, aclacinomycin is effective in controlling erythroid differentiation of K562, a human erythroleukemic cell line. To better understand early events implicated in this process, we have used bisindolylmaleimide (GF109203X), an inhibitor with a high selectivity for protein kinase C (PKC). Our data show that GF109203X inhibits aclacinomycin effects on K562, evidenced by a strong reduction of hemoglobinized cells and a marked decrease of mRNA rates of erythroid genes. To establish firmly PKC involvement, we also verified that aclacinomycin stimulates its rapid translocation, from the cytosolic to the membrane compartment. By Western blot analysis, we also show that after short induction times, PKCalpha was the most implicated.

[Targeting chemotherapy of hepatocellular carcinoma by arterial administration of anticancer agents dissolved in lipiodol].

The lipid lymphographic agent, Lipiodol ultrafluid has been found to remain selectively in hepatocellular carcinoma. Using this characteristic nature of Lipiodol, a new targeting anticancer chemotherapy was devised. In order to achieve targeting anticancer chemotherapy and useful anticancer effects, anticancer drugs must be dissolved or suspended in Lipiodol and diffuse out from the Lipiodol gradually. Oily anticancer agents such as SMANCS dissolved in Lipiodol (SMANCS/Lipiodol), Mitomycin C in Lipiodol (MMC/Lipiodol), Aclarubicin in Lipiodol (ACR/Lipiodol) and a mixture of these were administered by catheterizing the celiac or hepatic artery under X-ray monitoring in 216 patients with hepatocellular carcinoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in 91% of cases. The survival period of patients with unresectable hepatoma treated with the present protocol was definitely longer than the comparison group.

Enhancement of NK-cell activity in normal and tumor-bearing mice after administration of aclacinomycin.

Aclacinomycin (ACM) a new cytotoxic antibiotic employed in cancer chemotherapy, can either enhance or inhibit the NK-cell activity of the immune system, depending on the dose administered. A single intraperitoneal injection of 2-4 mg/kg of ACM augments the cytolytic activity by spleen and peritoneal exudate cells of normal mice and spleen cells depleted of nylon-adherent cells and peritoneal exudate cells of tumor-bearing mice. In contrast to the stimulatory effect of NK-cell activity by low doses of ACM, a single injection of 8 mg/kg of this agent leads to depression in the level of NK-cell activity in both normal and tumor-bearing animals. We suggest that the mechanism through which the ACM enhances NK-cell activity may be through the deletion of a suppressor cell population acting on the NK cells.

Experimental studies on aclacinomycin.

Experimental features of aclacinomycin (ACM), a new antitumour antibiotic of the anthracycline group, are presented. ACM inhibited the growth of experimental mouse tumours and human cancer xenografts from various origins. In CDF1 mice with L1210 cells treated i.p. with ACM in combination with Ara-C for 10 days, a 459% ILS was observed, including 67% of 60-day survivors. The inhibition of RNA and DNA synthesis was examined in L1210 cells. The IC50 values of ACM for incorporations of [14C]-thymidine and [14C]-uridine were 0.30 and 0.038 microgram/ml respectively. The ratio of IC50. DNA/RNA was 7.9, while with adriamycin (ADR) it was 2.5. ACM showed no mutagenic activity in the Ames' test and the rec- assay. The cardiac toxicity of ACM was significantly lower than that of ADR. Lower ECG changes, a return to normal after discontinuation of the drug and slighter ultrastructural modifications of the myocardium were demonstrated in hamsters and rabbits. When administered to hamsters i.v. at 5 mg/kg, ACM was eliminated almost completely from the heart muscle after 2 h, while ADR remained at 8 micrograms/g even after 8 h.

[Low molecular weight immunomodulators produced by microorganisms].

Immunomodulatory and antitumor activities of the low molecular weight, microbially-derived immunomodulators, bestatin and forphenicinol are reviewed. In addition, the inhibitory effects of the antitumor antibiotics, aclacinomycin and oxanosine, on the generation of suppressor cells are also represented. It is suggested that these substances will be useful for cancer treatment by chemotherapy and/or immunotherapy.