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Determinants of Intrinsic Sensitivity to Vinca Alkaloids in Xenografts of Pediatric Rhabdomyosarcomas¹

Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

The determinants of intrinsic sensitivity to Vinca alkaloids in vivo were examined in 3 pediatric rhabdomyosarcoma xenografts maintained s.c. in immune-deprived mice. The three lines differed in their sensitivity to VCR and VLB: two lines (Rh12 and Rh28) were extremely sensitive to VCR, whereas Rh18 tumors were less sensitive. Rh28 tumors were also very responsive to VLB, which demonstrated only marginal activity in the other two lines. After administration of equimolar doses (3 mg/kg) of [³H]-VCR and [³H]VLB to tumor-bearing mice. [³H]VCR reached concentrations approaching 1.5 µM in cell water of each tumor line within 4 hr, at which time >93% of the drug was cell-associated. The drug was subsequently retained at this level for at least 72 hr studied. [³H]VLB accumulated to lower maximal concentrations (1 µM) within 8 hr, but was not retained and, by 72 hr, reached concentrations that were 3- to 4-fold lower than those of [³H]VCR. The extent of drug retention correlated with the antitumor activity except in Rh28 tumors, which were sensitive to VLB, but did not retain the drug. The threshold level for achieving cytotoxicity may, thus, be very low in this line. In normal tissues, maximal concentrations of both [³H]VCR and [³H]VLB were achieved within 1 hr of administration i.p. to tumorbearing mice. In ileum, liver, and kidney, these were approximately 10-fold higher than the peak levels achieved within tumors or plasma, but declined rapidly to parallel the decrease in plasma reaching concentrations >5-fold lower than the concentration of [³H]VCB in tumors at 72 hr after treatment. Drug concentrations in skeletal muscle also declined rapidly, whereas neither [³H]VCR nor [³H]VLB accumulated to any great extent in brain. The blood volumes of ileum, kidney, and liver were greater than for tumor tissues. Hence, the extent of drug delivery did not necessarily influence therapeutic selectivity. In the case of [³H]VLB, concentrations in tumors approached those of normal tissues at 72 hr after injection. At 24 hr after treatment, 86 to 99% of [³H]VCR and 78 to 90% of [³H]VLB were present in tumors as the parent compound, which also predominated in normal tissues. Metabolites or in vivo degradation products were also identified.

Selective retention in tumors appears to be the mechanism by which therapeutic selectivity is achieved with VCR in rhabdomyosarcoma xenografts. The general lack of metabolism by normal tissues suggests that metabolism may not influence retention in these tissues. The importance of the interaction of these agents with tubulin in different tissues as well as factors influencing drug retention are discussed.

¹ This work was supported by Grant CH-156 from the American Cancer Society, Grant CA 23099 from the National Cancer Institute, and by American Lebenese Syrian Associated Charities.

² To whom requests for reprints should be addressed, at Department of Biochemical and Chical Pharmacology, St. Jude's Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.

Received 8/29/83. Accepted 11/ 3/83.

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