Antiangiogenic, antitumoural and antimetastatic effects of two distamycin A derivatives with anti-HIV-1 Tat activity in a Kaposi's sarcoma-like murine model.
The antiangiogenic, antitumoural and antimetastatic effects of two novel sulphonic derivatives of distamycin A, PNU145156E and PNU153429, were studied in a Kaposi's sarcoma-like tumour model obtained by injecting nude mice with cells releasing extracellular HIV-Tat protein, derived from a tumour which developed in a BK virus/tat transgenic mouse. Both PNU145156E and PNU153429 were administered intraperitoneally every fourth day for three weeks at doses of 100 or 50 mg/kg of body weight respectively, starting one day after injecting the tumour cells. Both drugs delayed tumour growth in nude mice, preventing neovascularization induced by the Tat protein. PNU153429 also significantly reduced the number and size of spontaneous tumour metastases. Both effects on tumour growth and metastases were augmented by treating simultaneously nude mice with 7.5 mg/kg of body weight of minocycline given per os daily for four weeks starting four days after injecting the tumour cells. Neither acute nor chronic toxic side-effects were observed during the life span of treated nude mice. Due to their antiangiogenic and anti-Tat effects, these drugs are promising for the treatment of Kaposi's sarcoma in AIDS patients.
Possati
L
L
Institute of Biomedical Sciences, University of Ancona, Italy. possati@popcsi.unian.it
Campioni
D
D
Sola
F
F
Leone
L
L
Ferrante
L
L
Trabanelli
C
C
Ciomei
M
M
Montesi
M
M
Rocchetti
R
R
Talevi
S
S
Bompadre
S
S
Caputo
A
A
Barbanti-Brodano
G
G
Corallini
A
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004214:Distamycins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D015756:Genes, tat; D015497:HIV-1 / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008911:Minocycline / Q000008:administration & dosage; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004214:Distamycins; C085720:FCE 26644; D015696:Gene Products, tat; D009363:Neoplasm Proteins; C113015:PNU 153429; D054322:tat Gene Products, Human Immunodeficiency Virus; D008911:Minocycline