The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.

No abstract

The anti-MUC1 antibody, CTM01, has been chosen to target the potently cytotoxic calicheamicin antitumor antibiotics to solid tumors of epithelial origin that express this antigen. Earlier calicheamicin conjugates relied on the attachment of a hydrazide derivative to the oxidized carbohydrates that occur naturally on antibodies. This produced a "carbohydrate conjugate" capable of releasing active drug by hydrolysis in the lysosomes where the pH is low. Conjugates have now been made that are formed by reacting a calicheamicin derivative containing an activated ester with the lysines of antibodies. This gives an "amide conjugate" that is stable to hydrolysis, leaving the disulfide that is present in all calicheamicin conjugates as the only likely site of drug release from the conjugate. As previously shown for the carbohydrate conjugate, this amide conjugate of CTM01 produces complete regressions of xenograft tumors at doses of 300 microg/kg (calicheamicin equivalents) given three times. This indicates that hydrolytic drug release is not necessary for potent, selective cytotoxicity for calicheamicin conjugates of CTM01. Although the unconjugated calicheamicins are in general less active in cells expressing the multidrug resistance phenotype, both in vitro and in vivo results of studies reported here suggest that the efficacy of the calicheamicins toward such tumors is unexpectedly enhanced by antibody conjugation, especially for the "amide conjugate". These hydrolytically stable conjugates are also active toward cisplatin-resistant ovarian carcinoma cells as well. Such studies indicate that the calicheamicin amide conjugate of CTM01 may have potential for the treatment of MUC1-positive solid tumors, including some types of resistant tumors.

Mitoxantrone (Novantrone; dihydroxyanthracenedione) belongs to a new structural class of antineoplastic agents, the anthracenediones. It was the outcome of a program in synthetic chemistry, at the Medical Research Division of the American Cyanamid Company, which started from a molecule with structural features predicted to favor intercalation with double stranded DNA. The initial lead compound had immunomodulatory effects and was subsequently found also to possess significant activity against transplantable murine tumors. A large series of analogues was synthesized and mitoxantrone was selected for clinical trial on the basis of its potency and excellent antitumor activity in mice. It is a cytotoxic agent that will kill both proliferating and non-proliferating cells. A variety of experiments conducted with both intact cells and cell-free systems have revealed mitoxantrone's ability to bind to single stranded and double stranded RNA and DNA. The drug inhibits cellular RNA and DNA synthesis to about the same extent and causes chromosomal aberrations. In vivo experiments using murine models have demonstrated good activity for mitoxantrone against a variety of transplantable tumors including both leukemias and solid types, in many cases giving putative cures. Surprisingly, it is effective when given up to 30 days before tumor implantation. Combination studies with standard anticancer agents gave evidence of therapeutic synergy in a number of cases. Preclinical studies in several animal models indicate that mitoxantrone does not have the cumulative cardiotoxic liability associated with anthracycline antibiotics such as doxorubicin.

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