title: Cytostatic and immunomobilizing activities of polymer-bound drugs: experimental and first clinical data.
abstract: An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing doxorubicin and human immunoglobulin as an actively/passively targeting moiety was used in four patients with generalized breast cancer resistant to standard cytotoxic chemotherapy. The dose and time schedule were deduced from a Phase I clinical trial in which doxorubicin bound to HPMA copolymer carrier (PK1) was tested. It was confirmed that the Dox-HPMA-HuIg conjugate is stable and doxorubicin remains in the peripheral blood with a small amount also in the urine, mostly in its polymer-bound form. More than 116 biochemical, immunological and hematological parameters were determined for blood samples taken from patients 24 h, 48 h, 72 h and 1 to 11 weeks after treatment. Depending on the patient, some parameters decreased permanently or temporarily to the normal level (CRP, C3, CA 72-4, beta(2)-microglobulin, ferritin, CEA, CA 125, CD4, CD8, CE19, CD16(+)56(+), leu, ery) and some moved markedly towards physiological values (AST, ALT, ALP, GMT, CA 15-3, NSE, AFP). While the number of peripheral blood reticulocytes was significantly decreased after treatment with the classical free drug, their number was not affected or was even elevated after treatment with Dox-HPMA-HuIg. Increased absolute numbers of CD16(+)56(+) and CD4(+) cells in the peripheral blood and activation of NK and LAK cells in all patients support data obtained in experimental animals, pointing to a dual, i.e. cytostatic and immunomobilizing character of Dox-HPMA conjugates containing a targeting immunoglobulin moiety.
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 4, Prague, Czech Republic. rihova@biomed.cas.cz
authors.forename: Blanka
authors.initials: B
authors.lastname: Ríhová
authors.forename: Jirí
authors.initials: J
authors.lastname: Strohalm
authors.forename: Jana
authors.initials: J
authors.lastname: Prausová
authors.forename: Katerina
authors.initials: K
authors.lastname: Kubácková
authors.forename: Markéta
authors.initials: M
authors.lastname: Jelínková
authors.forename: Lad'ka
authors.initials: L
authors.lastname: Rozprimová
authors.forename: Milada
authors.initials: M
authors.lastname: Sírová
authors.forename: Dana
authors.initials: D
authors.lastname: Plocová
authors.forename: Tomás
authors.initials: T
authors.lastname: Etrych
authors.forename: Vladimír
authors.initials: V
authors.lastname: Subr
authors.forename: Tomás
authors.initials: T
authors.lastname: Mrkvan
authors.forename: Marek
authors.initials: M
authors.lastname: Kovár
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
mesh_terms: D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001772:Blood Cell Count; D001943:Breast Neoplasms / Q000188:drug therapy / Q000601:surgery; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005079:Excipients; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007136:Immunoglobulins / Q000737:chemistry; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects; D008111:Liver Function Tests; D008408:Mastectomy; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008875:Middle Aged; D011108:Polymers; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005079:Excipients; D007074:Immunoglobulin G; D007136:Immunoglobulins; D008689:Methacrylates; D011108:Polymers; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate; D013936:Thymidine