Cancer Chemotherapy

Ratain, Mark J.; Ewesuedo, Reginald

doi:10.1007/978-3-642-97988-0_3

Cited by 2 publications

(6 citation statements)

References 212 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Paclitaxel induces neutropenia, hypersensitivity reactions, peripheral neuropathy and cardiac rhythm disturbances (Rowinsky and Donehower, 1995;Ratain, 1997). Docetaxel is associated with fluid retention and skin toxicity and, although nausea, vomiting and diarrhoea may be observed, severe gastrointestinal toxicity is rare (Ratain, 1997).…”

Section: Raltitrexed With Taxanesmentioning

confidence: 99%

“…They have several postulated mechanisms of action, the most important of which is believed to be interference with the function of the enzyme topoisomerase II (Ratain, 1997). A representation of the action of anthracyclines is shown in Figure 3.…”

Section: Raltitrexed With Anthracyclinesmentioning

confidence: 99%

“…5-FU, 5-fluorouracil Dose-limiting toxicity of the anthracyclines manifests chiefly as myelosuppression, with neutrophils being primarily affected. Gastrointestinal toxicity, including mucositis, is also common (Ratain, 1997). It should be noted that mucositis is markedly less severe with raltitrexed than with 5-FU (Cunningham et al, 1996a) which may make raltitrexed the more suitable of these two TS inhibitors for such a combination study.…”

Section: Raltitrexed With Anthracyclinesmentioning

confidence: 99%

“…Platinum-containing compounds act by cross-linking (adduction) with DNA strands (cisplatin reacts readily with the purine N7 position to form a variety of mono-and bifunctional DNA adducts, the majority of which are intrastrand cross-links) (Ratain, 1997). The resulting damage to DNA strands (including local kinking and unwinding) causes inhibition of transcription and replication ( Figure 5).…”

Section: Raltitrexed With Platinum Compoundsmentioning

confidence: 99%

“…Cisplatin is the longest-established drug of this type but is associated with severe toxicity (nausea and vomiting, nephrotoxicity, myelosuppression, neurotoxicity and ototoxicity). Oxaliplatin is a third-generation compound that causes minimal myelosuppression and has not been associated with nephrotoxicity; toxicity manifests mainly as nausea and vomiting, diarrhoea and neurotoxicity (Ratain, 1997). These agents have been combined with 5-FU in pretreated patients with resistant tumours, most notably oxaliplatin in patients with advanced CRC (Levi et al, 1992(Levi et al, , 1994(Levi et al, , 1995de Gramont et al, 1994).…”

Section: Raltitrexed With Platinum Compoundsmentioning

confidence: 99%

See 4 more Smart Citations

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex')

Blackledge

1998

Br J Cancer

View full text Add to dashboard Cite

Summary Following the demonstration of efficacy, tolerability and quality-of-life benefits of raltitrexed ('Tomudex'), principally in advanced colorectal but also in other cancers, an extensive evaluation of combination therapy with other agents in patients with colorectal and other tumour types is being undertaken. This work has been prompted by preclinical observations of enhanced activity of raltitrexed when coadministered with other cytotoxic agents or radiotherapy and by preliminary results showing the activity of raltitrexed in patients with cancers other than colorectal. Raltitrexed is currently being investigated as monotherapy in phase and 11 cancer studies, including head and neck cancer, hormone-resistant prostate cancer, paediatric and adult leukaemias and solid tumours, and soft tissue sarcoma. In addition, phase clinical trials are evaluating the drug in combination with taxanes (paclitaxel) in solid tumours, anthracyclines (doxorubicin) in gastric carcinoma, topoisomerase inhibitors (CPT-11) and 5-fluorouracil (both infusion and bolus regimens) in advanced colorectal cancer, platinum compounds (oxaliplatin and cisplatin) in a variety of tumours and radiotherapy in rectal cancer. Preliminary reports indicate good tolerability and acceptability of the combinations being investigated, with no dose-limiting toxicity being reported to date, and some early indications of efficacy.Keywords: raltitrexed; combination therapy; monotherapy; synergism; additivity Raltitrexed ('Tomudex') has been designed to inhibit directly and non-competitively a specific molecular target, thymidylate synthase (TS). The development of TS inhibitors for cancer therapy has been described in several reviews (Jackman and Judson, 1996;Touroutoglou and Pazdur, 1996;Rustum et al, 1997). TS converts deoxyuridine monophosphate (dUMP) into thymidine monophosphate (TMP), after which other enzymes convert TMP to thymidine triphosphate, a key requirement for DNA synthesis. 5-Fluorouracil (5-FU) is metabolized to 5-fluorodeoxyuridine monophosphate (FdUMP), which forms an inactive complex with TS and stops the synthesis of TMP by blocking access of dUMP to TS. However, the concentration of dUMP in the cell then rises to the point at which it is able to overcome FdUMP. 5-FU is also converted to other metabolites that can affect RNA and subsequently protein synthesis; these may enhance antitumour activity but may also cause toxicity. Unlike 5-FU, raltitrexed inhibits TS directly and does not require the presence of a second agent (Figure 1) (Jackman et al, 1995). Furthermore, the drug is specific for TS and does not appear to affect other cellular pathways. Raltitrexed is taken up into cells by the reduced folate carrier system in the cell membrane. This carrier is found more frequently on some tumour cells, an observation that may help to explain the selectivity of raltitrexed. While raltitrexed is active in its parent form, once inside the cell it is rapidly converted into polyglutamated forms. These polyglutamates are more potent inhibito...

show abstract

Section: Raltitrexed With Taxanesmentioning

confidence: 99%

Section: Raltitrexed With Anthracyclinesmentioning

confidence: 99%

Section: Raltitrexed With Anthracyclinesmentioning

confidence: 99%

Section: Raltitrexed With Platinum Compoundsmentioning

confidence: 99%

Section: Raltitrexed With Platinum Compoundsmentioning

confidence: 99%

See 3 more Smart Citations

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex')

Blackledge

1998

Br J Cancer

View full text Add to dashboard Cite

show abstract

Protective effects of Ficus racemosa stem bark against doxorubucin-induced renal and testicular toxicity

2013

View full text Add to dashboard Cite

Background:Ficus racemosa Linn. (Moraceae) bark is a rich source of phenolic compounds known to possess potential antioxidant activity offering numerous health benefits.Materials and Methods:The present study evaluated the protective effects of sequential acetone extract of Ficus racemosa bark at two doses (FR250; 250 mg kg-1 and FR500; 500 mg kg-1 p.o.) against doxorubicin-induced renal and testicular toxicity in rats.Results:Doxorubicin administration resulted in significant decrease (P ≤ 0.05) in total protein and glutathione concentrations, while increased (P ≤ 0.05) serum urea, creatinine and thiobarbituric acid reactive substances (TBARS). Extract pretreatment restored biochemical parameters toward normalization. FR250 and FR500 decreased serum creatinine levels by 22.5% and 44%, while serum urea levels were decreased by 30.4% and 58.8%, respectively. Extract pretreatment (500 mg kg-1) decreased TBARS and increased glutathione levels in the kidney and testis to control levels. These observations were substantiated by histopathological studies, wherein normal renal and testicular architecture was restored in FR500 group.Conclusion:Doxorubicin exposure results in pronounced oxidative stress, and administration of F. racemosa stem bark extract offers significant renal and testicular protection by inhibiting lipidperoxidation-mediated through scavenging free radicals.

show abstract

Cancer Chemotherapy

Cited by 2 publications

References 212 publications

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex')

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex')

Protective effects of Ficus racemosa stem bark against doxorubucin-induced renal and testicular toxicity

Contact Info

Product

Resources

About