About This Project

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What is the context of this research?

While long term survival rate of pediatric cancer improved significantly, life-long side effects of chemotherapy remains a substantial issue. Investigators from the Childhood Cancer Survivor Study estimated a cumulative incidence of 73.4% for at least one chronic condition health problem. Forty percent will experience a chronic condition that is severe, life-threatening, or fatal.

Antitumor drugs used in pediatrics, including the alkylating agent ifosfamide, carboplatin, cisplatin, and high dose methotrexate (HD-MTX) have strong nephrotoxic effects. Ifosfamide is incorporated into chemotherapy protocols for the treatment of Ewing’s sarcoma, osteosarcoma, soft tissue sarcomas, rhabdomyosarcoma, testicular tumors, and relapsed Wilms' tumor.

Although efficacious, 5-13% of the pediatric patients treated with ifosfamide alone, and over 25% of the children treated with combinations of ifosfamide and carboplatin experience clinically serious nephropathy. When renal toxicity is severe, it tends to be chronic. Risk factors for nephrotoxicity include high cumulative dose, young age, previous or concurrent cisplatin treatment, and unilateral nephrectomy. Nephrotoxicity is one of the serious dose-limiting complications of MTX when used in the treatment of various pediatric malignancies.

N–acetylcysteine (NAC) acts as a thiol antioxidant by scavenging reactive oxygen species such as O2•-, H2O2, and •OH. NAC has demonstrated protective effects on the kidneys in cisplatin - and cyclosporine-induced nephrotoxicity in experimental systems. Recent animal studies and clinical case reports, demonstrated that NAC is an effective renoprotective medication for ifosfamide -induced nephrotoxicity. NAC may also be a promising agent against HD-MTX-induced renal damage and can prevent cis-diamminedichloroplatinum-induced ototoxicity, nephrotoxicity, and gastrointestinal toxicity.

Although including NAC seems logical to protect non-timorous tissue from chemotherapy, the important question of whether NAC compromises the antitumor activity of ifosfamide, carboplatin and HD-MTX has not been adequately answered. To ensure safe use NAC as a renoprotector in pediatric chemotherapy, we need to try it in animal cancer model to ensure that the preventive treatment does not compromise antitumor activity of chemotherapy.

We will start with an animal model of B-cell lymphoma, will treat mice with HD-MTX and NAC and evaluate it’s benefit.

If successful, we will extend the study for the other tumors (Ewing’s sarcoma, osteosarcoma, soft tissue sarcomas, rhabdomyosarcoma, testicular tumors et ctr) and chemotherapeutic agents (ifosfamide, carboplatin, cisplatin).

What is the significance of this project?

Recent study showed that impaired glomerular function is one of the health problems affecting childhood cancer survivors: the loss in glomerular function starts early, especially for those treated with ifosfamid, higher doses of cisplatin, and nephrectomy.

Children appear at higher risk of nephrotoxicity than adults because of metabolic differences associated with maturation. Children under three-years-old are more susceptible to the nephrotoxic effects than older children. A progressive increase in renal tubular toxicity is observed with succeeding courses of chemotherapeutic treatment. With initial courses, tubular function returns to normal between courses, but eventually function declines and does not return to baseline; in some patients this tubulopathy becomes permanent. Glomerular function may also be affected. Irreversible damage might lead to the need for dialysis and renal transplant.

Kidney damage more often happens in children treated for Ewing’s sarcoma, osteosarcoma, soft tissue sarcomas, rhabdomyosarcoma and lymphomas. Approximately 650 children are diagnosed with osteosarcoma and Ewing’s sarcoma each year. Five-year survival rates range from 65-75% for localized Ewing’s sarcoma. A large international trial is currently investigating the effectiveness of ifosfamide/etoposide therapy for the treatment of osteosarcoma. Similarly, 850-900 children are diagnosed with soft tissue sarcomas and treated with ifosfamide-containing protocols each year.

If using N–acetylcysteine we protect normal cells and improve long-term well-being of the pediatric cancer survivors, it will be a huge step forward toward safer chemotherapeutic treatment.

What are the goals of the project?

The design of a safe and effective treatment protocol, which prevents nephrotoxicity while providing effective cancer treatment, is an important endpoint of our proposed work.

The main goal of the study is to ensure that N–acetylcysteine (NAC) does not interfere with the antitumor activity of chemotherapeutic agents, while providing renoprotection. Pre-clinical studies to confirm the fact are required before NAC inclusion in standard treatment protocols can be evaluated in clinical trials.

Donors, will be acknowledged in publications.