[Chemotherapeutic characterization of new nitrosourea compounds].
The development of new nitrosoureas is described using selected examples. Results obtained with water-soluble analogs and with compounds linked to biomolecules as for instance amino acids, oligopeptides and steroids, are presented. The pronounced antineoplastic effect of some water-soluble analogs is paralleled by an increased rate of DNA-interstrand cross-links and by an increased suppression of hematopoietic stem cells. The suppression of bone marrow stem cells is followed by their rapid regeneration. Water-soluble nitrosoureas induce significant less inhibition of glutathione reductase as compared with established compounds. With regard to long-term toxicity and carcinogenicity water-soluble are superior to established compounds as for instance BCNU. Linking of the nitrosourea moiety to amino acids and oligopeptides led to some analogs with outstanding therapeutic ratio. Out of a group of steroid-linked nitrosoureas, CNC-L-alanine-estradiol-17-ester (CNC-ala-17-E2) is chosen to demonstrate the possibility of reducing bone marrow toxicity despite unchanged or increased therapeutic activity by attachment of the nitrosourea moiety to a steroid. Results of a comparative interspecies in vitro evaluation of CNC-ala-17-E2 in transplanted MXT mammary carcinoma of the mouse, MNU-induced autochthonous rat mammary carcinoma and primary human mammary carcinomas are presented and the question is discussed to what extent in vitro activity of such receptor agents using the tumor stem cell assay reflects their in vivo activity.
Institut für Toxikologie und Chemotherapie, Deutsches Krebsforschungszentrum, Heidelberg.
W J
WJ
Zeller
M R
MR
Berger
G
G
Eisenbrand
E
E
Petru
D000818:Animals; D000970:Antineoplastic Agents; D001943:Breast Neoplasms / Q000188:drug therapy; D004338:Drug Combinations; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D005260:Female; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D009607:Nitrosourea Compounds / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D012995:Solubility; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004338:Drug Combinations; D009607:Nitrosourea Compounds; D005980:Glutathione Reductase
Chemotherapeutische Charakterisierung neuer Nitrosoharnstoffe.