Reduced lethality in mice receiving a combined dose of cyclophosphamide and busulphan

Summary.-Cyclophosphamide (Cy) produces an interstitial pneumonitis in CBA mice. The extent of the lung damage has been quantified by measuring the increase in ventilation rate over 6 weeks after an i.p. injection of Cy 200,250 and 300 mg/kg. A dose-dependent response was found. When a preliminary ("priming") dose of Cy at 50 mg/kg was given 7, 9 or 14 days before a single large dose of 250 mg/kg, lung damage was reduced, as shown by a smaller increase in ventilation rate than in those receiving 250 mg/kg alone, and this difference was significant (P < 0 01) in the Day-14-and highly significant (P<0-001) in the Day-7-"primed" groups. When primed less than 7 days before, there was a relative increase in ventilation rate, which was statistically significant (P <0.01) in the Day-i -primed group. Similar effects were also seen in the survival of the mice.

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cyclophosphamide-induced lung damage in mice: protection by a small preliminary dose

Collis¹,

Wilson²,

Jones³

1980

“…These data were generated from survival curves for MY-CFUc and GM-CFUC following melphalan treatment made on the same bone marrow aspirates from each patient. Myeloma cells were designated resistant to melphalan if the ratio of the doses of melphalan required to reduce the surviving fraction to 10% between MY-CFU, and GM-CFU, was 4 or greater (Millar et al, 1989 Since all patients receive cyclophosphamide (400 mg m-2) 7 days before HDM to enhance the recovery of normal bone marrow progenitors (Millar et al, 1975) (Bonnet et al, 1982;Kyle et al, 1982). Also, patients in CR have measurable disease using anti-idiotypic antibodies to detect the residual myeloma clone (Stevenson & Thompson, 1988) despite the restoration of normal haemopoiesis and absence of detectable paraprotein.…”

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confidence: 99%

“…The concept that scheduling cytotoxic drugs in specific sequences may enhance the recovery of normal tissue has been established for more than a decade (Millar et al, 1975;Millar & McElwain, 1978). In animal models this phenomenon has not been accompanied by sparing of tumour tissue (Evans et al, 1983 Since both plasmacytoid and lymphoplasmacytoid myeloma cells formed MY-CFU, in vitro from patients at first and second relapse, we cannot claim to predict the future response at second relapse of these patients to chemotherapy based on the emergence of lymphoplasmacytoid cells.…”

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confidence: 99%

Evidence that multiple myeloma may be regulated by homeostatic control mechanisms: correlation of changes in the number of clonogenic myeloma cells in vitro with clinical response

Maitland

Millar²,

Bell³

et al. 1990

Myeloma colonies (MY-CFUc) could be grown in vitro for 6 months (median time) after a group of 12 myeloma patients had reached complete remission (CR). In a second group of 25 patients MY-CFUc increased in 17/25 and GM-CFUc in 20/25 patients after cyclophosphamide even though 24/25 patients had a partial response to VAMP and one was in CR. These data suggest that cell killing by cyclophosphamide stimulates residual tumour cells into proliferation and adds further support to the idea that myeloma is under some degree of homeostatic control which may be analogous to that in normal bone marrow. Although lymphoplasmacytoid myeloma cells may be more drug resistant than plasmacytoid myeloma cells in vitro, it was not possible to conclude that the emergence of lymphoplasmacytoid cells at relapse was indicative of resistance to further treatment.

“…These combinations generally take the form of a small dose (the pretreatment or priming dose) followed by a large challenge dose of the same (Jeney et al, 1968;Rose et al, 1975;Millar and McElwain, 1978) or different cytotoxic agent Jeney et al, 1968;Schmidt et al, 1970: Millar et al, 1975Millar and Hudspith 1976;Millar et al, 1978).…”

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confidence: 99%

Effect of high-dose melphalan on marrow and intestinal epithelium in mice pretreated with cyclophosphamide

Millar¹,

Hudspith²,

McElwain³

et al. 1978

Self Cite

Summary.-The lethal effect of high-dose melphalan in mice could be offset by pretreatment with cyclophosphamide, cytosine arabinoside or low-dose melphalan. The reason for improved survival is unclear. Although animals given high-dose melphalan died with symptoms of gut death, in only one instance, that with low-dose melphalan itself, did pretreatment protect the intestinal epithelium as measured by the microcolony assay. A small enhancement in the recovery of the haemopoietic tissue in pretreated animals was noted, although this on its own is unlikely to explain the phenomenon. Experiments in tumour-bearing mice showed that pretreatment with cyclophosphamide did not reduce the toxicity of melphalan to the Lewis lung carcinoma.