Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as “lead” compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

Natural products as leads to anticancer drugs.

Background Recently, increasing numbers of women receiving adjuvant chemotherapy for breast cancer have also received granulocyte colony-stimulating factors (G-CSFs) or granulocyte-macrophage colony-stimulating factors (GM-CSFs). Although these growth factors support chemotherapy, their long-term safety has not been evaluated. We studied the association between G-CSF use and incidence of leukemia in a population-based sample of breast cancer patients. Methods Among women aged 65 years or older in the Surveillance, Epidemiology, and End Results-Medicare database who were diagnosed with stages I-III breast cancer from January 1, 1991, to December 31, 1999, we identified those who received G-CSF or GM-CSF concurrently with chemotherapy. We used Cox proportional hazards models to estimate hazard ratios for the association of treatment with G-CSF or GM-CSF and subsequent (through December 31, 2003) diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). All statistical tests were two-sided. Results Of 5510 women treated with chemotherapy, 906 (16%) received G-CSF or GM-CSF therapy, and 64 (1.16%) were subsequently diagnosed with either MDS or AML before a cancer recurrence. Use of G-CSF and GM-CSF was associated with more recent diagnosis, younger age, urban residence, fewer comorbidities, receipt of radiation therapy, positive lymph nodes, and cyclophosphamide treatment. Of the 906 patients who were treated with G-CSF, 16 (1.77%) developed AML or MDS; of the 4604 patients not treated with G-CSF, 48 (1.04%) developed AML or MDS. The hazard rate ratio for AML or MDS among those treated with G-CSF or GM-CSF compared with those who were not was 2.14 (95% confidence interval [CI] = 1.12 to 4.08). AML or MDS developed within 48 months of breast cancer diagnosis in 1.8% of patients who received G-CSF or GM-CSF but only in 0.7% of patients who did not (hazard ratio = 2.59, 95% CI = 1.30 to 5.15). Conclusions The use of G-CSF was associated with a doubling in the risk of subsequent AML or MDS among the population that we studied, although the absolute risk remained low. Even if this association is confirmed, the benefits of G-CSF may still outweigh the risks. Meanwhile, however, G-CSF use should not be assumed to be risk free.

/pdf/acute-myeloid-leukemia-or-myelodysplastic-syndrome-following-sn4biui1qt.pdf

Acute Myeloid Leukemia or Myelodysplastic Syndrome Following Use of Granulocyte Colony-Stimulating Factors During Breast Cancer Adjuvant Chemotherapy

Diarrhoea and constipation are common toxicities of chemotherapy, and both are poorly understood. They are manifestations of alimentary mucositis, a condition which affects the entire gastrointestinal tract. The absolute percentage of patients that have diarrhoea or constipation as a result of their treatment has yet to be fully defined, although general estimates place 10% of patients with advanced cancer as being afflicted. Although there has been some major progress in recent years with understanding the mechanisms of oral and small intestinal mucositis, diarrhoea and constipation have received very little attention. Although diarrhoea is a well-recognised side-effect of both chemotherapy and radiotherapy, very little research has been conducted on the mechanisms behind diarrhoea or its treatment. Much of the information in the published literature is based on clinical observations with very little basic science existing. Constipation is not as well recognised and very little is known about its mechanisms. This review will examine in detail the potentially complex pathogenesis of post-chemotherapy diarrhoea in both animal models and the clinical setting. Furthermore, it will explore what is known about chemotherapy-induced constipation. It will then outline an evidence-based pathway for the investigation and treatment of post-chemotherapy diarrhoea and constipation.

Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies

Summary The past 10 years have seen substantial advances in molecularly targeted therapies for treatment of patients with cancer; however, chemotherapy will continue to be used. Therefore, the toxic effects of chemotherapy must be readily managed—especially nausea, vomiting, mucositis, and diarrhoea. For moderately to highly emetogenic chemotherapy, standard prophylactic treatment is an antagonist for 5-hydroxytryptamine 3 receptors (5-HT3R) combined with dexamethasone for the acute phase, and dexamethasone with another agent for prevention of the delayed phase. Palonoestron (a 5-HT3R antagonist) and aprepitant (an antagonist for the protachykinin 1 receptor) have been introduced for the prevention of emesis. Other agents such as cannabinoids, gabapentin, and olanzapine might also be effective. There is no standard prophylactic regimen for chemotherapy-induced mucositis. The most common treatment is optimum care of the mouth by use of mouthwashes. Keratinocyte growth factor, molgromastim, and transforming growth factor β3 may also reduce chemotherapy-induced mucositis. Severe diarrhoea is another potentially fatal complication of chemotherapy and is most common in patients treated with irinotecan. Several interventions have been assessed for prevention and treatment of diarrhoea such as high-dose loperamide, non-absorbable antibiotics, budesonide, thalidomide, and fish oils, but only loperamide is used routinely. Symptom management has become a focus of clinical research, and development of personalised medicine should identify patients at increased risk of toxic effects because of molecular or biochemical factors, thus leading to changes in dose, early intervention, or use of alternative therapies.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(05)01735-3.pdf

Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea.

Background: One of the most common toxicities of cancer treatment is diarrhoea. Probiotics have been shown effective at preventing diarrhoea in inflammatory bowel disease and may prove useful in the oncology setting. Aim: The primary aim of this study was to investigate the probiotic mixture, VSL#3, for amelioration of chemotherapy-induced diarrhoea (CID). Methods: This experiment was carried out in a clinically relevant model of CID. VSL#3 was administered to female DA rats in one of three schedules. Irinotecan was used to induce mucositis and diarrhoea, with rats monitored for 7 days to record incidence of weight-loss and diarrhoea. At study completion, intestines were collected to investigate histological and proliferative changes, apoptosis levels and mucin composition. Results: VSL#3 reduced weight loss following irinotecan when administered before and after chemotherapy. Moderate and severe diarrhoea was also prevented in these rats. This was associated with a significant increase in crypt prolifera...

VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss.

Incidence of chemotherapy-induced amenorrhea depending on the timing of treatment by menstrual cycle phase in women with early breast cancer

High serum levels of TNF-α and IL-6 predict the clinical outcome of treatment with human recombinant erythropoietin in anaemic cancer patients

Does the concurrent use of anthracycline and granulocyte colony-stimulating factor influence the risk of secondary leukaemia in breast cancer women?

Can Colorectal Cancer Patients With Thymidylate Synthase–Overexpressing Liver Metastases Have an Overall Survival Advantage With Hepatic Arterial Infusion Alone?

Subacute motor weakness and left renal mass

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