Management of locally advanced cervical cancer

Rojas-Espaillat, Luis; Rose, Peter G.

doi:10.1097/01.cco.0000174049.14515.8d

Cited by 16 publications

(11 citation statements)

References 56 publications

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“…Concomitant chemotherapy and irradiation is the standard treatment for advanced squamous cell cervical cancer [164,165], but neoadjuvant chemotherapy followed by radical hysterectomy with pelvic lymphadenectomy appears to be an effective therapeutic option for patients with stages Ib 2 -IIb disease [166,167]. TIP regimen is associated with a higher optimal pathologic response rate than the combination of IFO + CDDP, without any statistically significant benefit on overall survival [167].…”

Section: Discussionmentioning

confidence: 99%

Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer

Gadducci

Cionini

Romanini

et al. 2006

Critical Reviews in Oncology/Hematology

104

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Section: Discussionmentioning

confidence: 99%

Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer

Gadducci

Cionini

Romanini

et al. 2006

Critical Reviews in Oncology/Hematology

104

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“…Calpain Inhibitor VI Synergized with Cisplatin-Cisplatin is extensively used in the treatment of cervical cancer (32), is able to up-regulate p53 expression in HPV-transformed cells (33), and promotes p53-mediated apoptosis (34). Calpain inhibitors are being developed to treat a range of diseases (16) including cancer (17), and we have shown that calpain inhibitor VI is able to inhibit the growth of HeLa or Caski cell xenographs in Foxn1 nu mice (supplemental Fig.…”

Section: A Calpain Inhibitor Restored Rb Protein Levels Repressed E6mentioning

confidence: 99%

“…Cisplatin combined with radiotherapy has become the standard treatment for locally advanced cervical cancer and can achieve survival rates of Ͼ70% (32). For women with disseminated, persistent, recurrent, or metastatic disease, few treatment options exist (42).…”

Section: Why Might This Two-step Process For Rb Degradation Havementioning

confidence: 99%

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Darnell

Schroder

Antalis

et al. 2007

Journal of Biological Chemistry

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Cervical cancers transformed by high risk human papilloma virus (HPV) express the E7 oncoprotein, which accelerates the degradation of the retinoblastoma protein (Rb). Here we show that the E7-mediated degradation of Rb requires the calciumactivated cysteine protease, calpain. E7 bound and activated -calpain and promoted cleavage at Rb 810 , with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb 1-810 , was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Infection with high risk human Papillomavirus (HPV)2 types is responsible for virtually all cases of cervical cancer, which is currently the second most common cause of death from cancer among women worldwide (1). Vaccination will likely have a substantial impact; however, current modeling suggests that it may take 40 -50 years to reach an Ϸ50% reduction in mortality (2). Integration of part of the HPV genome is believed to be central to the transformation process (3) and often results in the increased expression of the two viral oncoproteins, E6 and E7. A principle activity of E6 and E7 is promotion of the accelerated degradation of p53 and the retinoblastoma protein (Rb), respectively (4, 5). Hypophosphorylated Rb binds the E2F transcription factor, resulting in repression of E2F-dependent gene transcription and G 1 cell cycle arrest (6). The promotion of Rb degradation mediated by E7 is believed to involve a two-step process (7). First, E7 binds hypophosphorylated Rb (8), which leads to the displacement of E2F and entry into the cell cycle. How E2F is displaced by E7 remains unclear as E7 and E2F binding sites on Rb have recently been shown to be quite distinct (9). The second step involves E7 targeting Rb for accelerated degradation via the proteasome (10 -12). A new insight into the mechanism of E7-mediated degradation of Rb was recently provided by our observation that the serine protease inhibitor SerpinB2 was able to inhibit E7-mediated degradation of Rb in HeLa cells (13,14). There are no reports that SerpinB2 inhibits the proteasome, and it has recently emerged that SerpinB2 inhibits calpain-mediated degradation of Rb. 3Calpains represent a group of calcium-activated cysteine proteases, two of which, -calpain and m-calpain, are ubiquitously expressed and found both in the cytoplasm and the nucleus (15). Herein we provide evidence that the first step in the E7-mediated degradation of Rb involves calpain cleavage. E7 was shown to bind and activate -calpain and promoted cleavage of full-length Rb 1-928 to yield Rb . Rb 1-810 was unable to promote cell cycle arrest, suggesting that this cleavage event was sufficient to displace E2F from Rb. The second step involved the promotion by E7 of the proteasomal degradation of Rb . Calpain inhibitors are being developed for a number of diseases including cancer (16, 17) and were able to inhibit E7-mediated degradation of Rb. They also reduced the viability of HPV-tr...

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“…La definición de cáncer cérvico uterino localmente avanzado incluye a pacientes con etapa IB2 a IVA (7). La cirugía no es una opción terapéu-tica para pacientes con etapa IIB, III y IV debido a una elevada proporción de márgenes positivos y factores de alto riesgo de recidiva, aumentando la utilización de radioterapia postoperatoria, incrementando la morbilidad asociada al tratamiento.…”

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Manejo Del Cáncer Cérvico Uterino Localmente Avanzado

2006

Rev. chil. obstet. ginecol.

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RESUMENEl cáncer cérvico uterino es uno de los cánceres invasores más comunes en países subdesarrollados. Esfuerzos para mejorar resultados de tratamiento utilizando quimioterapia neoadyuvante, adyuvante y concomitante con radioterapia han sido probados. Cinco estudios randomizados y 2 meta-análisis que estudiaron radioquimioterapia basado en cisplatino han demostrado ventajas significativas en sobrevida. Basado en los resultados de estos cinco estudios randomizados el National Cancer Institute realizó un anuncio clínico apoyando el uso de radioquimioterapia basada en cisplatino como el nuevo tratamiento estándar para cáncer cérvico uterino localmente avanzado. Aunque estos avances en el tratamiento han mejorado la proporción de curación de mujeres con enfermedad localmente avanzada un gran porcentaje de pacientes morirán por recidiva local y/o metástasis a distancia. Esta revisión evaluará críticamente la evidencia que apoya las modalidades de tratamiento disponibles para cáncer cérvico uterino localmente avanzado.PALABRAS CLAVES: Radioquimioterapia, cáncer cérvico uterino localmente avanzado, quimioterapia neoadyuvante, cisplatino, tratamiento multimodal SUMMARYCervical cancer is one of the most common invasive neoplasia in women in underdeveloped countries. In an effort to improve treatment outcomes neoadjuvant chemotherapy, adjuvant and concurrent chemoradiation has been tested. Five randomized trials and two meta-analysis studying cisplatin-based chemoradiation have demonstrated a significant survival advantage. Based on the results of these five randomized trials the National Cancer Institute released a clinical announcement stating that cisplatin-based chemoradiotherapy as the new standard therapy for locally advanced cervical cancer. Although these treatment advances have improved the cure rate for women with locally advanced cervical cancer, a large percentage of women will die of locally recurrent and metastatic cancer. This review will critically evaluate the evidence supporting the available treatment modalities for locally advanced cancer of the uterine cervix.

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Management of locally advanced cervical cancer

Abstract: Continued improvement in understanding the natural history of cervical cancer, the limitations of the current staging system, and these newer therapeutic options will increase the efficacy of chemoradiation and improved the survival of these patients.

Cited by 16 publications

References 56 publications

Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer

Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Manejo Del Cáncer Cérvico Uterino Localmente Avanzado

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