Aldo Tagliabue

The effects of adriamycin and daunomycin on antitumoral immune effector mechanisms in an allogeneic system.

Abstract C3H mice pretreated with adriamycin (AM) 24 hr before transplantation with the allogeneic L1210 leukemia had a significantly longer survival than mice given an equitoxic dose of its analog daunomycin (DM). The effect of the two drugs on cellular and humoral immune effector mechanisms was thus investigated. The longer surviving AM-pretreated tumor allografted mice were found to have higher levels of cell-mediated cytotoxicity (CMC) in the peritoneal cavity, e.g., at the site where tumor growth was actually occurring. On the contrary when spleen CMC was investigated, either no differences were seen or DM-hosts had higher cytotoxic activity. DM was also found to cause a faster impairment than AM of the spleen capacity to mediate antibodydependent cellular cytotoxicity (ADCC). As regards humoral responses, serum complement-dependent and arming activity were absent in both test groups, whereas higher levels of potentiating activity were found in AM pretreated hosts. The possible significance of the lower impairment of antitumoral immune effector mechanisms in giving AM its superior antineoplastic effectiveness is discussed.

Effects of adriamycin and daunomycin on spleen cell populations in normal and tumor allografted mice.

Abstract In the attempt to elucidate the complex differential interaction of adriamycin (AM) and daunomycin (DM) with immune reactivity, the effects of these agents on spleen cell subpopulations were investigated in normal and tumor-allografted drugpretreated mice. In terms of total organ cellularity, DM induced a faster and longer lasting cell-depletion than AM, although the nadir values were similar for both drugs. The percentages of theta positive and EA-rosette forming cells (EA-RFCs) were not modified by the two drugs in normal animals, whereas the increase in percent EA-RFCs observed in control tumor allografted mice was partially inhibited by both drugs. Macrophages were relatively spared by these agents as evidenced by an increase in their percent value.

Combination chemo-immunotherapy with adriamycin in experimental tumor systems☆

Abstract The possibility of integrating adriamycin (Adria) in combined chemoimmunotherapeutic treatments with non-specific immunomodulators was investigated. With an appropriate choice of treatment conditions clear synergistic effects were observed in the L 1210 Ha leukemia when Adria was followed by treatment with Corynebacterium parvum (C. parvum) , BCG and levamisole; however the Adria- C. parvum combination was found to be the most active. C. parvum appeared additionally to exert better antitumoral activity in this system when associated with Adria than with other antitumorals given in equiactive doses. The high therapeutic activity of the Adria- C. parvum combination was confirmed in three other leukemia systems (P 388 , LSTRA, L 1210 Cr) even in conditions where chemotherapy with Adria alone was ineffective. Clear beneficial effects were additionally seen with this combination in the solid spontaneously metastatizing Lewis lung carcinoma, a system in which the triple therapeutic approach surgery-Adria- C. parvum was more effective than either of the binary combinations. The potential clinical implications of these results and the possible mechanisms at the basis of the synergism between Adria and C. parvum are discussed.

Effect of Corynebacterium parvum on cellular and humoral antitumoral immune effector mechanisms

Abstract In an attempt to characterize the mechanism of action of Corynebacterium parvum (C. parvum) an analysis was performed of the changes in specific antitumoral immune effector mechanisms in C3H mice showing increased protection against challenge with high inocula of the allogeneic L1210 leukemia after treatment with this immunoadjuvant. C. parvum-treated spleens displayed an increase in DNA synthesis, total cell number and in the percentage of macrophages; the percent of theta bearing lymphocytes was concomitantly decreased whereas no modification in the percent of EA-rosette forming cells was observed. Although the efficiency of target cell lysis by immune splenocytes was unchanged, the raise in spleen cellularity of C. parvum-treated mice resulted in a marked increase in this organs capacity to express cell-mediated cytotoxicity. Treatment with this adjuvant produced also a sizable increase in the spleen capacity to mediate antibody-dependent cellular cytotoxicity whereas arming and potentiating serum activities and the levels of complement-dependent cytolytic antibody were not modified.

The immunostimulatory activity of 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazole [3, 2-α]-benzimidazole-2-acetic acid (NSC 208828)☆

Abstract A preliminary characterization of 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo [3,2-α]-benzimidazole-2-acetic acid was conducted in mice employing tumorous and non-tumorous systems. Single doses of this chemical markedly increased the primary and secondary anti-SRBC response after optimal immunization and raised the GvH-inducing capacity of splenocytes whereas no effects were seen on the response to a T-independent antigen. Immunostimulatory doses of the drug did not modify colloidal carbon clearance, macrophage non-specific cytotoxicity towards lymphoma cells or K cell activity in the spleen. Single injections with this agent increased survival in L 1210Ha leukemia-bearing mice when administered in conjunction with irradiated tumor cells and increased anti-leukemia resistance to subsequent tumor challenges in animals primed with inactivated leukemia cells. Single drug doses 1 day after tumor transplantation exerted also a potent antimetastatic effect in the Lewis lung carcinoma system.

Variation among mouse strains in responsiveness to migration inhibitory factor

Abstract Mineral oil-induced peritoneal exudate cells (PEC) from 10 different inbred mouse strains were tested for their responses to macrophage migration inhibitory factor (MIF). PEC from 5 out of 10 mouse strains responded to MIF, PEC from BALB/c mice showed an intermediate responsiveness, and PEC from A/J, C3H/HeJ, CBA/N, and C57BL/10ScCR mice were refractory to MIF. MIF responsiveness was not linked to the H-2 complex. However, a possible link between responsiveness to LPS and MIF was suggested, since the mouse strains not responding to MIF were previously reported to be deficient for responses to LPS.