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1.
Anticancer Drugs ; 32(1): 61-65, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32701559

RESUMO

The pharmacologically active metabolite of cyclophosphamide is aldophosphamide. With cysteine, aldophosphamide forms stable aldophosphamide-thiazolidine which under physiological pH and temperature conditions hydrolyzes to aldophosphamide and cysteine. Aldophosphamide-thiazolidine was synthesized and tested for its ability as a cytostatic. The LD50 after a single intraperitoneal injection in mice was determined to be 2162 mg/kg, but after intravenous bolus administration of 500 mg/kg or in chronic toxicity tests with daily intraperitoneal injections, neurological side effects were observed. Antitumor activity was determined in therapy experiments in CD2F1 mice bearing subcutaneously transplanted P388 mouse leukemia cells. Administration of 100 mg/kg (less than 5% LD50) days 1-5 after tumor transplantation yielded an ILS of 100%. Organ distribution studies showed that aldophosphamide-thiazolidine is evenly distributed in all tissues examined, including brain tissue. The possibilities to increase the antitumor activity of aldophosphamide-thiazolidine by modulating the alkylating function are discussed.


Assuntos
Barreira Hematoencefálica/metabolismo , Citostáticos/farmacologia , Leucemia Experimental/tratamento farmacológico , Compostos de Mostarda Nitrogenada/farmacologia , Tiazolidinas/farmacologia , Animais , Apoptose , Barreira Hematoencefálica/efeitos dos fármacos , Proliferação de Células , Citostáticos/farmacocinética , Feminino , Leucemia Experimental/metabolismo , Leucemia Experimental/patologia , Camundongos , Compostos de Mostarda Nitrogenada/farmacocinética , Tiazolidinas/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas
2.
Anticancer Drugs ; 31(6): 617-622, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044797

RESUMO

Cyclophosphamide is an inert prodrug converted into 4-hydroxycyclophosphamide (OHCP) by hepatic hydroxylation. OHCP is in equilibrium with its tautomeric aldophosphamide (ALDO). From ALDO, the cytotoxic active metabolites are formed enzymatically by phosphodiesterases; these are the alkylating metabolite phosphoramide mustard (PAM) and the proapoptotic aldehyde 3-hydroxypropanal (HPA). PAM damages the DNA by alkylation; HPA amplifies the thereby induced apoptosis. The generally accepted view that acrolein, which is believed to be formed in the formation of PAM by ß-elimination from ALDO would be mainly responsible for the toxicity of cyclophosphamide, has to be revised because no acrolein is formed in the systemic circulation of patients after cyclophosphamide administration. It is shown that not acrolein, but OHCP itself is the true toxic metabolite of cyclophosphamide. Toxicity tests with OHCP and PAM were carried out, which demonstrated that OHCP unfolds its toxicity, not as a carrier of PAM but is toxic itself by reacting with nucleophilic groups of macromolecules, for example, thiol groups of membrane proteins. Further experiments demonstrate that the toxicity of oxazaphosphorine cytostatics may be drastically reduced if the formation of the pharmacologically active metabolite ALDO bypasses the formation of OHCP. Toxicity experiments in mice with S-ethanol-cyclophosphamide (SECP) that hydrolyzes to OHCP show that SECP is as toxic as OHCP, whereas the thiazolidine of ALDO, which hydrolyzes to ALDO bypassing OHCP is 7-9 times less toxic without loss of antitumor activity.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/análogos & derivados , Ciclofosfamida/toxicidade , Leucemia P388/patologia , Mostardas de Fosforamida/toxicidade , Animais , Antineoplásicos Alquilantes/química , Ciclofosfamida/química , Feminino , Leucemia P388/tratamento farmacológico , Masculino , Camundongos , Mostardas de Fosforamida/química , Testes de Toxicidade
3.
Anticancer Drugs ; 30(5): 435-440, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30855309

RESUMO

On the basis of the discovery that the proapoptotic aldehyde 3-hydroxypropanal is a cyclophosphamide metabolite, a novel mechanism of action of oxazaphosphorine cytostatics is presented and confirmed by animal experiments. Furthermore, it is shown that new oxazaphosphorine cytostatics, which are on orders of magnitude more effective than already existing, can be developed on the basis of the new model for the mechanism of action.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/farmacologia , Citostáticos/farmacologia , Desenho de Fármacos , Ifosfamida/farmacologia , Compostos Organofosforados/farmacologia , Animais , Humanos
4.
Anticancer Drugs ; 29(5): 411-415, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29465464

RESUMO

SUM-IAP is an aldo-ifosfamide-perhydrothiazine derivative that, under physiological conditions, spontaneously hydrolyzes to SUM-aldo-ifosfamide. In SUM-IAP, one 2-chloroethyl group of the alkylating function of aldo-ifosfamide-perhydrothiazine is substituted by a mesyl-ethyl group. The compound was synthesized to investigate the influence of the alkylating function of aldo-ifosfamide on the antitumor activity of oxazaphosphorine cytostatics. In chemotherapy experiments in CD2F1 mice with advanced subcutaneously growing P388 mice leukemia cells, the primary tumor was reduced below the detection level with two highly dosed injections on days 7 and 8, but after 14 days, the primary tumor was measurable again. The primary tumor and detectable metastases killed the animals 29-30 days after SUM-IAP application. When, however, the animals were treated again with two highly dosed injections on day 14 and 15, a 4-5 times increase in the number of leukocytes was measured and all animals survived the observation period of 100 days. In the high, cancer-reductive dose range, SUM-IAP is not only a cytotoxic but also an immunostimulating oxazaphosphorine cytostatic.


Assuntos
Antineoplásicos/farmacologia , Compostos Organofosforados/farmacologia , Tiazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/imunologia , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Fatores Imunológicos/farmacologia , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/patologia , Contagem de Leucócitos , Metástase Linfática/patologia , Camundongos Endogâmicos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/imunologia , Tiazinas/administração & dosagem , Tiazinas/imunologia
5.
Anticancer Drugs ; 29(1): 75-79, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29219879

RESUMO

The present work investigates the influence of different DNA damages caused by different isophosphoramide mustards on the 3-hydroxypropanal-assisted apoptotic antitumor activity of oxazaphosphorine cytostatics using I-aldophosphamide-perhydrothiazine (IAP) and mesyl-I-aldophosphamide-perhydrothiazine (SUM-IAP) for in-vitro and in-vivo experiments. IAP and SUM-IAP hydrolyze spontaneously to the corresponding I-aldophosphamide derivatives. They differ in the chemical structure of the alkylating moiety, whereas IAP has two chlorethyl groups in the SUM-IAP molecule, one chlorethyl group is substituted by a mesylethyl group. With both substances, cytotoxicity studies on P388 tumor cells in vitro and therapy experiments in mice bearing advanced growing P388 tumors were carried out. IAP was significantly more cytotoxic in-vitro than SUM-IAP, but the antitumor activity of SUM-IAP was by order of magnitude higher than the antitumor activity of IAP. The reason for these findings is discussed with respect to the enzymatic cleavage of the various I-aldophosphamide derivatives to the corresponding isophosphoramide mustards and 3-hydroxypropanal. Overall, the findings indicate that antitumor activity of ifosfamide and derivatives of ifosfamide can be improved considerably by altering the alkylating moiety of the molecule, but retaining the aldophosphamide structure.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Ifosfamida/farmacologia , Leucemia Experimental/tratamento farmacológico , Animais , Dano ao DNA , Feminino , Ifosfamida/análogos & derivados , Camundongos
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