In vivo, synergestic inhibition of MAT-LyLu rat prostatic adenocarcinoma growth by polyamine deprivation and low-dose cyclophosphamide.
Polyamine deprivation in vivo produces significant tumor growth inhibition of the hormone-resistant, metastatic Dunning Mat-LyLu murine prostatic carcinoma. In order to produce a cytotoxic effect in addition to the cytostatic effect of polyamine deprivation, various chemotherapy regimens, combined with drug-containing polyamine-deficient chow (DC-PDC), were assessed. Triple chemotherapy combining methotrexate, cyclophosphamide and vindesine; and monochemotherapy with high-dose cyclophosphamide (90 mg. kg-1) and low-dose cyclophosphamide (20 mg.kg-1) were studied alone and in combination with DC-PDC. A variant of DC-PDC excluding the polyamine oxidase inhibitor MDL 72527 was also studied in combination with low-dose cyclophosphamide. The triple-chemotherapy regimen alone or in combination with polyamine deprivation was effective on tumor growth inhibition but was also toxic. High-dose cyclophosphamide alone produced significant tumor growth inhibition and an increase in life span. High-dose cyclophosphamide in combination with DC-PDC was also effective on tumor growth but was also toxic. Low-dose cyclophosphamide alone was moderately effective on tumor growth inhibition with a marginal increase in life span. When combined with polyamine deprivation, results with low-dose cyclophosphamide compared favourably with those of high-dose cyclophosphamide alone and prevented the formation of lung metastases. The polyamine oxidase inhibitor does not appear to be mandatory to achieve this effect if DC-PDC is combined with low-dose cyclophosphamide. Polyamine deprivation appears to be an important tool in anticancer therapy, allowing the use of reduced doses of cytotoxic agents with the same antitumoral efficacy.
Cipolla
B
B
Service d'Urologie, CHU de Rennes, Hôpital de Pontchaillou, France.
Blanchard
Y
Y
Chamaillard
L
L
Quemener
V
V
Guillé
F
F
Havouis
R
R
Moulinoux
J P
JP
D000230:Adenocarcinoma / Q000401:mortality* / Q000628:therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000518:Eflornithine / Q000494:pharmacology; D008175:Lung Neoplasms / Q000178:diet therapy / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008795:Metronidazole / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D011073:Polyamines / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000401:mortality* / Q000628:therapy*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015996:Survival Rate
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D011073:Polyamines; D011500:Protein Synthesis Inhibitors; D008795:Metronidazole; C044445:MDL 72527; D003520:Cyclophosphamide; D000587:Oxidoreductases Acting on CH-NH Group Donors; D009355:Neomycin; D011700:Putrescine; D000518:Eflornithine