title: Oncobiguanides: Paracelsus' law and nonconventional routes for administering diabetobiguanides for cancer treatment.
abstract: "The dose makes the poison", the common motto of toxicology first expressed by Paracelsus more than 400 years ago, may effectively serve to guide potential applications for metformin and related biguanides in oncology. While Paracelsus' law for the dose-response effect has been commonly exploited for the use of some anti-cancer drugs at lower doses in non-neoplastic diseases (e.g., methotrexate), the opposite scenario also holds true; in other words, higher doses of non-oncology drugs, such as anti-diabetic biguanides, might exert direct anti-neoplastic effects. Here, we propose that, as for any drug, there is a dose range for biguanides that is without any effect, one corresponding to "diabetobiguanides" with a pharmacological effect (e.g., insulin sensitization in type 2 diabetes, prevention of insulin-dependent carcinogenesis, indirect inhibition of insulin and growth factor-dependent cancer growth) but with minimal toxicity and another corresponding to "oncobiguanides" with pharmacological (i.e., direct and strong anticancer activity against cancer cells) as well as toxic effects. Considering that biguanides demonstrate a better safety profile than most oncology drugs in current use, we should contemplate the possibility of administering biguanides through non-conventional routes (e.g., inhaled for carcinomas of the lung, topical for skin cancers, intravenous as an adjunctive therapy, rectal suppositories for rectal cancer) to unambiguously investigate the therapeutic value of high-dose transient biguanide exposure in cancer. Perhaps then, the oncobiguanides, as we call them here, could be viewed as a mechanistically different type of anti-cancer drugs employed at doses notably higher than those used chronically when functioning as diabetobiguanides.
authors.affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.forename: Rosa
authors.initials: R
authors.lastname: Quirantes-Piné
authors.forename: Esther
authors.initials: E
authors.lastname: Rodríguez-Gallego
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.forename: Antonio
authors.initials: A
authors.lastname: Segura-Carretero
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008687:Metformin / Q000008:administration & dosage* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008687:Metformin