Mechanisms of Resistance

Purpose 4’-Thio-β-D-arabinofuranosylcytosine (4’-thio-ara-C), which has shown a broad spectrum of antitumor activity against human tumor systems in mice and is undergoing clinical trials, was evaluated for cross-resistance to seven clinical agents in order to identify potentially useful guides for patient selection for further clinical trials of 4’-thio-ara-C and possible noncross-resistant drug combinations with 4’-thio-ara-C. Methods A drug-resistance profile for 4’-thio-ara-C, which was administered intraperitoneally daily for nine consecutive days, was obtained using seven drug-resistant P388 and L1210 leukemias that were implanted intraperitoneally in mice. Results Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin, etoposide, or paclitaxel) exhibited no cross-resistance to 4’-thio-ara-C. Leukemias resistant to camptothecin, cisplatin, and 5-fluorouracil were also not cross-resistant to 4’-thio-ara-C. Only the leukemia resistant to 1-β-D-arabinofuranosylcytosine was cross-resistant to 4’-thio-ara-C. Conclusions The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-β-D-arabinofuranosylcytosine and (2) the lack of cross-resistance seen with 4’-thio-ara-C may contribute to therapeutic synergism when 4’-thio-ara-C is combined with other agents.

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Section: Resultsmentioning

confidence: 99%

Lack of in vivo cross-resistance with 4′-thio-ara-C against drug-resistant murine P388 and L1210 leukemias

Waud

Gilbert

Secrist

2010

Cancer Chemother Pharmacol

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“…Studies conducted with human and other murine (L1210, L5178Y, and P815) leukemia cells resistant to ara-C have revealed several mechanisms of resistance: decreased membrane nucleoside-binding sites, decreased deoxycytidine kinase activity, increased cytidine deaminase activity, and increased intracellular CTP and dCTP pools. [14,15] Clinical studies with acute myeloid leukemia (AML) indicate that resistance correlates best with increases in Downloaded by [Fondren Library, Rice University ] at 09:18 18 November 2014 DNA polymerase α and 5 -nucleotidase activities and decreases in hENT transporter. Other studies show that resistance correlates with decreased deoxycytidine kinase and increased deoxycytidine deaminase activities.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of a Murine P388 Leukemia Line Resistant to Thiarabine

Waud

Parker

Gilbert

et al. 2012

Nucleosides, Nucleotides and Nucleic Acids

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A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara-C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias.

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“…On the basis of experimentail studies, the limited effectiveness for chemotherapy has been attributed to such factors as rapid repair of DNA damage,'",'' small growth fractions in tumors treated,I2," spontaneous drug resistance, 14. I 5 and insufficient duration of effective plasma drug levels in the face of continuing cell proliferation.…”

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confidence: 99%

High-dose cyclophosphamide and high-dose 5-fluorouracil: A new first-line regimen for advanced breast cancer

Israël

Breau

Aguilera

1984

Cancer

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Thirty consecutive patients with metastatic breast cancer previously untreated by chemotherapy were given high‐dose cyclophosphamide (Cytoxan) and high‐dose 5‐fluorouracil (5‐FU) as first‐line therapy. Cyclophosphamide, 1200 mg/m2 was administered intravenously (IV) on day I and 5‐FU, 600 mg/m2 IV on days 1 through 5. Cycles were repeated every 21 days or on hematologic recovery. Twenty‐eight of the 30 patients achieved a remission (16 partial, and 12 complete). i.e., a response rate of 93%, and a complete response rate of 40%. The actuarial survival rate at 43 months was 52% for the population as a whole, and 68% for patients who achieved a complete response. Hematologic toxicity was relatively severe and the initial doses had to be reduced by 20% in all patients between the second and fifth courses. No deaths due to either infection or bleeding were seen due largely to intensive supportive care. It is concluded that increasing the doses of a small number of drugs of proven efficacy may be more useful than increasing the number of drugs given in lower doses. Furthermore, this approach spares other effective drugs for second‐line therapy.

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Mechanisms of Resistance

Cited by 38 publications

References 302 publications

Lack of in vivo cross-resistance with 4′-thio-ara-C against drug-resistant murine P388 and L1210 leukemias

Lack of in vivo cross-resistance with 4′-thio-ara-C against drug-resistant murine P388 and L1210 leukemias

Isolation and Characterization of a Murine P388 Leukemia Line Resistant to Thiarabine

High-dose cyclophosphamide and high-dose 5-fluorouracil: A new first-line regimen for advanced breast cancer

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